Abstract:

Objective:

To perform a systematic review of the main epigenetic aberrations involved in non-small cell lung carcinomas’ (NSCLC) diagnosis, progression, and therapeutics.

Materials and methods:

We performed a systematic review of the scientific literature on lung cancer epigenetics, focusing on NSCLC.

Results:

Several advances in the molecular study of classical epigenetic mechanisms and massive studies of lung cancer epigenome have contributed relevant new evidence revealing that various molecular complexes are functionally influencing genetic-epigenetic and transcriptional mechanisms that promote lung tumorigenesis (initiation, promotion, and progression), and are also involved in NSCLC therapy-resistance mechanisms.

Conclusion:

Several epigenetic complexes and mechanisms must be analyzed and considered for the design of new and efficient therapies, which could be fundamental to develop an integrated knowledge to achieve a comprehensive lung cancer personalized medicine.

Keywords:
non-small cell lung cancer; epigenetics; biomarkers; DNA

Resumen:

Objetivo:

Realizar una revisión sistemática y estructurada de las principales aberraciones epigenéticas involucradas en el diagnóstico, progresión y terapia del cáncer pulmonar de células no pequeñas (CPCNP).

Material y métodos:

Revisión sistemática de literatura científica sobre epigenética del cáncer pulmonar del grupo CPCNP.

Resultados:

El estudio de los diversos mecanismos epigenéticos y su impronta epigenética en el epigenoma del cáncer pulmonar han arrojado nuevas evidencias a nivel biológico, biomédico y médico-clínico del impacto que los mecanismos epigenético-transcripcionales promueven de manera activa y reversible sobre los procesos de tumorigénesis, progresión histopatológica y mecanismos de resistencia a la terapia oncológica pulmonar.

Conclusión:

Deben analizarse diferentes complejos y mecanismos epigenéticos para el estudio y diseño de esquemas nuevos y eficaces de terapia epigenética, los cuales podrían ser fundamentales para desarrollar un conocimiento integral en el desarrollo de la medicina personalizada en el cáncer pulmonar del grupo CPCNP.

Palabras clave:
carcinoma de pulmón de células no pequeñas; epigenética; biomarcadores; AND

Introduction

Lung cancer is the most lethal malignant disease worldwide, it is expected that the number of cases of this disease will increase in the next few years, particularly in developing countries.¹1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. https://doi.org/10.3322/caac.21492
https://doi.org/10.3322/caac.21492... Lung cancer has been classified in two major histopathological groups: small cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC) that represents 80 to 85% of the total lung cancer cases. According to its histology, the NSCLC can be classified in: large cell carcinomas (LCC) 10%, squamous cell carcinomas (SCC) 40%, and adenocarcinomas (AD) 40%.²2. Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer. 1995;75(suppl 1):191-202. NSCLC has also been grouped at the molecular level, according to a new genetic expression signature based on 42 differentially expressed genes (with a fold change >2.6) significant statistically (t test, P value <10⁻¹⁸, with FDR <10⁻¹⁶), highlighting in other propose genes: high molecular weight keratins (KRT), NKX2-1 (TITF1), TP63, and DSG3 (desmoglein 3), as a part of the new molecular classification for the human NSCLC-histological group.³3. Girard L, Rodriguez-Canales J, Behrens C, Thompson DM, Botros IW, Tang H, et al. An expression signature as an aid to the histologic classification of non-small cell lung cancer. Clin Cancer Res. 2016;22(19):4880-9. https://doi.org/10.1158/1078-0432.CCR-15-2900
https://doi.org/10.1158/1078-0432.CCR-15... Nevertheless, in the pulmonary oncological field, clinical oncological prognoses and therapies are based on the relevant functional driver genes associated with the biology of lung cancer, particularly: EGFR-gene mutations, EML4-ALK-genetic fusions,⁴4. Wang H, Zhang W, Wang K, Li X. Correlation between EML4-ALK, EGFR and clinicopathological features based on IASLC/ATS/ERS classification of lung adenocarcinoma. Medicine. 2018;97(26):e11116. https://doi.org/10.1097/MD.0000000000011116
https://doi.org/10.1097/MD.0000000000011... and others oncogenic drivers as: BRAF, HER2, ROS1, RET, FGFR1, and PI3K, in human NSCLC.⁵5. Zugazagoitia J, Molina-Pinelo S, Lopez-Rios F, Paz-Ares L. Biological therapies in nonsmall cell lung cancer. Eur Respir J. 2017;49(3):1601520. https://doi.org/10.1183/13993003.01520-2016
https://doi.org/10.1183/13993003.01520-2...

However, despite marginal advances in the diagnosis and oncological therapies, the clinical outcome and prognosis have room to improve significantly for patients. Therefore, the treatment specifically addressed to genetic-epigenetic targets for the applied lung translational oncological medicine is a priority for translational oncological medicine.

In this topic, high-performance epigenomic strategies have revealed a new picture of the complexity of the malignant cellular and molecular mechanisms of lung cancer, as well as their potential application as biomarkers, and NSCLC therapies.

Based on the definition of the National Cancer Institute (NCI, Dictionary of Cancer Terms), a biomarker is “a biomolecule identified in fluid-tissues as blood, and other body-fluids, as well as solid tissues, as a sign of a normal versus abnormal physiological condition and/or disease-processes”.⁶6. National Cancer Institute. Cancer.gov [web page] [cited May 3, 2019]. Available from: Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/biomarker
https://www.cancer.gov/publications/dict... The concept of Epigenetic-biomarkers has been incorporated in the personalized medicine as cancer-epigenetic drugs and/or epigenetic-target therapies. Therefore, tumor-biomarker functional and clinically may be used, as a determinant diagnostic and/or prognostic aggressive-malignancy guidance in cancer biology and clinical oncology research,⁷7. Kulasingam V, Diamandis EP. Strategies for discovering novel cancer biomarkers through utilization of emerging technologies. Nat Clin Pract Oncol. 2008;5:588-99. https://doi.org/10.1038/ncponc1187
https://doi.org/10.1038/ncponc1187... where epigenetic biomarkers will be widely used in lung tumor biology, oncological prognosis, overall survival, early-late recurrence, and/or therapy response in human NSCLC.⁸8. Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S, et al. DNA Methylation Markers and Early Recurrence in Stage I LungCancer . N Engl J Med. 2008;358(11):1118-28. https://doi.org/10.1056/NEJMoa0706550
https://doi.org/10.1056/NEJMoa0706550... ^,99. Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nature Biotechnol. 2010;28(10):1069-78. https://doi.org/10.1038/nbt.1678
https://doi.org/10.1038/nbt.1678... ^,1010. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27-36. https://doi.org/10.1093/carcin/bgp220
https://doi.org/10.1093/carcin/bgp220...

Epigenetics in NSCLC

Most cases of NSCLC exhibit genetic alterations that have been widely described; however, a small number of NSCLC cases have been identified without genetic mutations and/or chromosomal-genomic aberrations in the fundamental oncological driver genes. The study of the three levels of the human cancer epigenome (DNA methylation, histone code modifications and nucleosome positioning) has allowed us to propose new molecular pathways in the hereditary epigenetic marks that accompany transient-reversible and hereditary permanent transcriptional states under normal conditions, embryonic development, non-malignant diseases and scenarios of malignant diseases.¹¹11. Mohammad HP, Baylin SB. Linking cell signaling and the epigenetic machinery. Nature Biotechnol . 2010;28:1033-8. https://doi.org/10.1038/nbt1010-1033
https://doi.org/10.1038/nbt1010-1033...

The first lung cancer epigenetic studies carried out by Issa and colleagues and Baylin and Herman between 1996 and 1998, reported emerging epigenetic biomarkers (Estrogen Receptor Gene-Promoter Methylation) in both, environmental carcinogenic lung cancer mice models, and lung carcinomas from smokers and never-smokers patients.¹²12. Issa JP, Baylin SB, Belinsky SA. Methylation of the estrogen receptor CpG island in lung tumors is related to the specific type of carcinogen exposure. Cancer Res. 1996;56(16):3655-8 Some of which have been proposed as early epigenetic events (increased DNA methyl-transferase activity) associated with lung carcinogenesis promotion and primary lung tumor progression.¹³13. Belinsky SA, Nikula KJ, Baylin SB, Issa JP. Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer. Proc Natl Acad Sci. 1996;93(9):4045-50. https://doi.org/10.1073/pnas.93.9.4045
https://doi.org/10.1073/pnas.93.9.4045... Where DNA methylation aberrations on driver-Tumor Suppressor Genes (p16INK4a) have been proposed in NSCLC (lung precursor lesions hyperplasias, adenomas, AD and SCC) as early epigenetic biomarkers with potential using in lung cancer diagnosis.¹⁴14. Swafford DS, Middleton SK, Palmisano WA, Nikula KJ, Tesfaigzi J, Baylin SB, et al. Frequent aberrant methylation of p16INK4a in primary rat lung tumors. Mol Cell Biol. 1997;17(3):1366-74. https://doi.org/10.1128/MCB.17.3.1366
https://doi.org/10.1128/MCB.17.3.1366... ^,1515. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, et al. Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci . 1998;95(20):11891-6. https://doi.org/10.1073/pnas.95.20.11891
https://doi.org/10.1073/pnas.95.20.11891... In addition, two decades ago, several emerging epigenetic disorders have been described and classified at DNA methylation, covalent histone modifications, and nucleosome remodeling levels on several oncogenic driver-genes (p16, H-Cadherin, RARb, APC, MGMT, RASSF1A, CDKN2A, SHOX2, etc.), persistently associated to lung cancer diagnosis and prognosis.¹⁶16. Balgkouranidou I, Liloglou T, Lianidou ES. Lung cancer epigenetics: emerging biomarkers. Biomark Med. 2013;7(1):49-58. https://doi.org/10.2217/bmm.12.111
https://doi.org/10.2217/bmm.12.111...

Moreover, in the last decade several oncological-research efforts have addressed large scale descriptive epigenetic studies, well-known as cancer epigenomics, into identify massive spreading altered epigenetic marks through -modulated-regulated- cancer epigenome, well known as functional epigenomics, into identify epigenetic-targets impacting on lung tumorigenesis, with its translational medicine implications.¹⁷17. Baylin SB. The cancer epigenome: its origins, contributions to tumorigenesis, and translational implications. Proc Am Thorac Soc. 2012;9(2):64-5. https://doi.org/10.1513/pats.201201-001MS
https://doi.org/10.1513/pats.201201-001M... On that subject, some new proposed molecular mechanisms involved in lung cancer histopathological progression, prognosis and efficient oncological-therapeutic protocols, have been proposed in NSCLC patients, using others epigenetic-inhibitors as Histone Deacetylases-inhibitors including Vorinostat plus cisplatin and paclitaxel, consolidating an epigenetic therapeutic field in NSCLC.¹⁸18. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, et al. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(1):56-62. https://doi.org/10.1200/JCO.2009.24.9094
https://doi.org/10.1200/JCO.2009.24.9094...

Epigenetics therapeutics in NSCLC

Based on the reversible nature of epigenetic modifications of methylated DNA and post-translational modifications of histones, some therapeutic strategies have been developed reversing malignancy in the cancer initiation, promotion and progression processes, consolidating the use of epigenetic biomarkers in the course and diagnosis of the malignant diseases.¹⁹19. Ahuja N, Sharma AR, Baylin SB. Epigenetic therapeutics: A new weapon in the war against cancer. Annu Rev Med. 2016 ;67(1):73-89. https://doi.org/10.1146/annurev-med-111314-035900
https://doi.org/10.1146/annurev-med-1113... ^,2020. Chervona Y, Costa M. Histone modifications and cancer: biomarkers of prognosis? Am J Cancer Res. 2012;2(5):589-97.^,2121. Seligson DB, Horvath S, McBrian MA, Mah V, Yu H, Tze S, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol. 2009;174(5):1619-28. https://doi.org/10.2353/ajpath.2009.080874
https://doi.org/10.2353/ajpath.2009.0808...

Three identifiable major molecular epigenetic patterns have been described at DNA epigenetic level: a) DNA global-hypomethylation, b) Region-specific DNA hypermethylation, and c) Genome-wide hypomethylation. These epigenetic aberration-modifications at epigenome-wide level, have led us to identify dysfunctional abilities on a) cellular-genetic expression patterns, b) physiological homeostasis of the cellular proliferation, and c) cellular-differentiation control. All of these cellular-disabilities, additionally respond to a higher functional complexity, affect chromatin remodeling complexes, nucleosome-assembling, histone code patterns, and epigenetic modulators epigenome-occupancy (figure 1).¹⁰10. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27-36. https://doi.org/10.1093/carcin/bgp220
https://doi.org/10.1093/carcin/bgp220... Some of these mechanisms have been proposed in lung-malignant diseases controlling transcription states, defining genetic expression levels and patterns, producing aberrations in the tumor-biomarker expression signatures through malignant tumorigenesis and histopathological progression compromising lung tissue at early and/or late NSCLC stages.¹⁶16. Balgkouranidou I, Liloglou T, Lianidou ES. Lung cancer epigenetics: emerging biomarkers. Biomark Med. 2013;7(1):49-58. https://doi.org/10.2217/bmm.12.111
https://doi.org/10.2217/bmm.12.111...

Based on this background, targeted-epigenetic therapeutic protocols have been proposed as strategies that reactivate and/or regulate transcriptional activity, by inhibiting epigenetic enzimes,⁹9. Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nature Biotechnol. 2010;28(10):1069-78. https://doi.org/10.1038/nbt.1678
https://doi.org/10.1038/nbt.1678... controlling oncogenes, tumor suppressor genes, and specific gene-signatures for each histopathological and molecular subtypes in NSCLC.³3. Girard L, Rodriguez-Canales J, Behrens C, Thompson DM, Botros IW, Tang H, et al. An expression signature as an aid to the histologic classification of non-small cell lung cancer. Clin Cancer Res. 2016;22(19):4880-9. https://doi.org/10.1158/1078-0432.CCR-15-2900
https://doi.org/10.1158/1078-0432.CCR-15... Thus, it is expected that in the near future there will be a better knowledge of the lung cancer epigenome (figure 1), and that these efforts will allow the development of therapies based on epigenetic drugs.¹⁷17. Baylin SB. The cancer epigenome: its origins, contributions to tumorigenesis, and translational implications. Proc Am Thorac Soc. 2012;9(2):64-5. https://doi.org/10.1513/pats.201201-001MS
https://doi.org/10.1513/pats.201201-001M...

Additional epigenetic-therapeutic strategies, have been based on the functional activity of the dynamic structure of chromatin, but centered on the enzymatic capacity of energy-dependent protein complexes leading to covalent post-translational modifications on the nucleosome, modulating several cellular processes, such as transcription, gene expression, as well as DNA recombination, replication and DNA damage repairing.²²22. Oike T, Ogiwara H, Amornwichet N, Nakano T, Kohno T. Chromatin-regulating proteins as targets for cancer therapy. J Radiat Res. 2014;55(4):613-28. https://doi.org/10.1093/jrr/rrt227
https://doi.org/10.1093/jrr/rrt227... ^,2323. Tyagi M, Imam N, Verma K, Patel AK. Chromatin remodelers: We are the drivers!! Nucleus. 2016 ;7(4):388-404. https://doi.org/10.1080/19491034. 2016 .1211217
https://doi.org/10.1080/19491034. 2016 ....

In this regard, some investigations have been conducted, using azacitidine (30-40 mg/m²/d) plus Entinostat (7 mg on days 3 and 10, each 28-day cycle) in phase I-II clinical trials with NSCLC patients.²⁴24. Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598-607. https://doi.org/10.1158/2159-8290.CD-11-0214
https://doi.org/10.1158/2159-8290.CD-11-... On these studies, gene-promoter hypermethylation status has been proposed as a quantitative negative prognostic factor (P< 0.001), based on the quantifiable DNA-Methylation on driver gene-promoter sequences, as APC, RASSF1A, CDH13, and CDKN2A in stage I and III NSCLC patients.⁸8. Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S, et al. DNA Methylation Markers and Early Recurrence in Stage I LungCancer . N Engl J Med. 2008;358(11):1118-28. https://doi.org/10.1056/NEJMoa0706550
https://doi.org/10.1056/NEJMoa0706550...

Additionally, in NSCLC, some mutations have been identified in genes codifying for the enzymatic subunits of the four classes of chromatin remodeling complexes (SWI/SNF, ISWI, CHD y INO80), such as ARID1A, BRG1, ARID2 and CHD7 (table I).²⁵25. Soca-Chafre G, Hernandez-Pedro N, Aviles-Salas A, Verson CA, Sanchez KC, Cardona AF, et al. Targeted next generation sequencing identified a high frequency genetic mutated profile in wood smoke exposure-related lung adenocarcinoma patients. Oncotarget. 2018;9(55):30499-512. https://doi.org/10.18632/oncotarget.25369
https://doi.org/10.18632/oncotarget.2536... ^,2626. Reisman DN, Sciarrotta J, Wang W, Funkhouser WK, Weissman BE. Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res. 2003;63(3):560-6.^,2727. Fukuoka J, Fujii T, Shih JH, Dracheva T, Meerzaman D, Player A, et al. Chromatin remodeling factors and BRM/BRG1 expression as prognostic indicators in non-small cell lung cancer. Clin Cancer Res. 2004;10(13):4314-24. https://doi.org/10.1158/1078-0432.CCR-03-0489
https://doi.org/10.1158/1078-0432.CCR-03... ^,2828. Medina PP, Carretero J, Fraga MF, Esteller M, Sidransky D, Sanchez-Cespedes M. Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors. Genes ChromosomesCancer . 2004;41(2):170-7. https://doi.org/10.1002/gcc.20068
https://doi.org/10.1002/gcc.20068... ^,2929. Wong AK, Shanahan F, Chen Y, Lian L, Ha P, Hendricks K, et al. BRG1, a component of the SWI-SNF complex, Is mutated in multiple human tumor cell lines. Cancer Res. 2000;60(21):6171-7.^,3030. Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J, Sanchez-Cespedes M. Frequent BRG1/SMARCA4-Inactivating mutations in human lung cancer cell lines. Hum Mutat. 2008;29(5)617-22. https://doi.org/10.1002/humu.20730
https://doi.org/10.1002/humu.20730... ^,3131. Rodriguez-Nieto S, Cañada A, Pros E, Pinto AI, Torres-Lanzas J, Lopez-Rios F, et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mutat. 2011;32(2):E1999-2017 . https://doi.org/10.1002/humu.21415
https://doi.org/10.1002/humu.21415... ^,3232. Medina PP, Carretero J, Ballestar E, Angulo B, Lopez-Rios F, Esteller M, et al. Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells. Hum Mol Gen. 2005;14(7):973-82. https://doi.org/10.1093/hmg/ddi091
https://doi.org/10.1093/hmg/ddi091... ^,3333. Orvis T, Hepperla A, Walter V, Song S, Simon J, Parker J, et al. BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization. Cancer Res. 2014;74(22):6486-98. https://doi.org/10.1158/0008-5472.CAN-14-0061
https://doi.org/10.1158/0008-5472.CAN-14... ^,3434. Bell EH, Chakraborty AR, Mo X, Liu Z, Shilo K, Kirste S, et al. SMARCA4/BRG1 Is a novel prognostic biomarker predictive of cisplatin-based chemotherapy outcomes in resected non-small cell lung cancer. Clin Cancer Res. 2016 ;22(10):2396-404. https://doi.org/10.1158/1078-0432.CCR-15-1468
https://doi.org/10.1158/1078-0432.CCR-15... ^,3535. Agaimy A, Fuchs F, Moskalev EA, Sirbu H, Hartmann A, Haller F. SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1(neg)/CK7(pos)/HepPar-1(pos) immunophenotype. Virchows Arch. 2017 ;471(5):599-609. https://doi.org/10.1007/s00428-017-2148-5
https://doi.org/10.1007/s00428-017-2148-... ^,3636. Meng J, Zhang XT, Liu XL, Fan L, Li C, Sun Y, et al. WSTF promotes proliferation and invasion of lung cancer cells by inducing EMT via PI3K/Akt and IL-6/STAT3 signaling pathways. Cell Signal. 2016 ;28(11):1673-82. https://doi.org/10.1016/j.cellsig. 2016 .07.008
https://doi.org/10.1016/j.cellsig. 2016 ... ^,3737. Wang CL, Wang CI, Liao PC, Chen CD, Liang Y, Chuang WY, et al. Discovery of retinoblastoma-associated binding protein 46 as a novel prognostic marker for distant metastasis in nonsmall cell lung cancer by combined analysis of cancer cell secretome and pleural effusion proteome. J Proteome Res. 2009;8(10):4428-40. https://doi.org/10.1021/pr900160h
https://doi.org/10.1021/pr900160h... ^,3838. Liu SL, Han Y, Zhang Y, Xie CY, Wang EH, Miao Y, et al. Expression of metastasis-associated protein 2 (MTA2) might predict proliferation in non-small cell lung cancer. Target Oncol. 2012;7(2):135-43. https://doi.org/10.1007/s11523-012-0215-z
https://doi.org/10.1007/s11523-012-0215-... ^,3939. Cao LL, Song X, Pei L, Liu L, Wang H, Jia M. Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer: A meta-analysis. Medicine. 2017 ;96(31):e7663. https://doi.org/10.1097/MD.0000000000007663
https://doi.org/10.1097/MD.0000000000007... ^,4040. Zhang L, Bu L, Hu J, Xu Z, Ruan L, Fang Y, et al. HDAC1 knockdown inhibits invasion and induces apoptosis in non-small cell lung cancer cells. J Biol Chem. 2018;399(6):603-10. https://doi.org/10.1515/hsz-2017 -0306
https://doi.org/10.1515/hsz-2017 -0306... ^,4141. Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Xie HJ, et al. HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. J Cell Biochem. 2012;113(6):2167-77. https://doi.org/10.1002/jcb.24090
https://doi.org/10.1002/jcb.24090... ^,4242. Li L, Mei DT, Zeng Y. HDAC2 promotes the migration and invasion of non-small cell lung cancer cells via upregulation of fibronectin. Biomed Pharmacother. 2016 ;84:284-90. https://doi.org/10.1016/j.biopha. 2016 .09.030
https://doi.org/10.1016/j.biopha. 2016 .... ^,4343. Luo W, Tian P, Wang Y, Xu H, Chen L, Tang C, et al. Characteristics of genomic alterations of lung adenocarcinoma in young never-smokers. Int JCancer . 2018;143(7):1696-705. https://doi.org/10.1002/ijc.31542
https://doi.org/10.1002/ijc.31542... ^,4444. Wang Y HN, Cheng X, Zhang J, Tan X, Zhang C, Tang Y, et al. Ezh2 Acts as a tumor suppressor in kras-driven lung adenocarcinoma. Int J Biol Sci. 2017 ;13(5):652-9. https://doi.org/10.7150/ijbs.19108
https://doi.org/10.7150/ijbs.19108... ^,4545. Behrens C, Solis LM, Lin H, Yuan P, Tang X, Kadara H, et al. EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clin Cancer Res. 2013;19(23):6556-65. https://doi.org/10.1158/1078-0432.CCR-12-3946
https://doi.org/10.1158/1078-0432.CCR-12... ^,4646. Xu C, Hou Z, Zhan P, Zhao W, Chang C, Zou J, et al. EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer. Med Oncol. 2013;30(4):713. https://doi.org/10.1007/s12032-013-0713-6
https://doi.org/10.1007/s12032-013-0713-... ^,4747. Vrzalikova K, Skarda J, Ehrmann J, Murray PG, Fridman E, Kopolovic J, et al. Prognostic value of Bmi-1 oncoprotein expression in NSCLC patients: a tissue microarray study. J Cancer Res Clin Oncol. 2008;134(9):1037-42. https://doi.org/10.1007/s00432-008-0361-y
https://doi.org/10.1007/s00432-008-0361-... ^,4848. Meng X, Wang Y, Zheng X, Liu C, Su B, Nie H, et al. shRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and metastasis. Lung cancer. 2012;77(1):24-30. https://doi.org/10.1016/j.lungcan.2012.02.015
https://doi.org/10.1016/j.lungcan.2012.0... Other mechanisms of resistance identified include altered function of SMARCE1 subunits of the SWI/SNF1 group, which conduce to overexpression of EGFR and contributing in resistance to inhibitors of MET and ALK in NSCLC;⁴⁹49. Papadakis AI, Sun C, Knijnenburg TA, Xue Y, Grernrum W, Holzel M, et al. SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer. Cell Res. 2015;25(4):445-58. https://doi.org/10.1038/cr.2015.16
https://doi.org/10.1038/cr.2015.16... the overexpression of BRG1 and BRM in the cisplatin toxicity,⁵⁰50. Kothandapani A, Gopalakrishnan K, Kahali B, Reisman D, Patrick SM. Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity. ExpCell Res . 2012;318(16):1973-86. https://doi.org/10.1016/j.yexcr.2012.06.011
https://doi.org/10.1016/j.yexcr.2012.06.... or doxorubicin chemo-resistance mechanisms associated with the expression of the subunits SMARCB1 and SMARCA4 (BRG1) in NSCLC cells.⁵¹51. Dubey R, Lebensohn AM, Bahrami-Nejad Z, Marceau C, Champion M, Gevaert O, et al. Chromatin-remodeling complex SWI/SNF controls multidrug resistance by transcriptionally regulating the drug efflux pump ABCB1. Cancer Res. 2016 ;76(19):5810-21. https://doi.org/10.1158/0008-5472.CAN-16-0716
https://doi.org/10.1158/0008-5472.CAN-16... This findings suggest the importance of the three main epigenetic mechanisms, DNA methylation, histone code modifications and chromatin remodeling complexes in cancer progression (table I and II).⁵²52. Armas-Lopez L, Pina-Sanchez P, Arrieta O, de Alba EG, Ortiz-Quintero B, Santillan-Doherty P, et al. Epigenomic study identifies a novel mesenchyme homeobox2-GLI1 transcription axis involved in cancer drug resistance, overall survival and therapy prognosis in lung cancer patients. Oncotarget. 2017 ;8(40):67056-81. https://doi.org/10.18632/oncotarget.17715
https://doi.org/10.18632/oncotarget.1771... ^,5353. Armas-Lopez L, Zuniga J, Arrieta O, Avila-Moreno F. The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy. Oncotarget . 2017 ;8(36):60684-703. https://doi.org/10.18632/oncotarget.19527
https://doi.org/10.18632/oncotarget.1952... ^,5454. Nishikawa E, Osada H, Okazaki Y, Arima C, Tomida S, Tatematsu Y, et al. miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. Cancer Res. 2011;71(19):6165-73. https://doi.org/10.1158/0008-5472.CAN-11-1020
https://doi.org/10.1158/0008-5472.CAN-11... ^,5555. Kikutake C, Yahara K. Identification of epigenetic biomarkers of lung adenocarcinoma through multi-omics data analysis. PloS one. 2016 ;11(4):e0152918. https://doi.org/10.1371/journal.pone.0152918
https://doi.org/10.1371/journal.pone.015... ^,5656. Ávila-Moreno F, Armas-López L, Álvarez-Moran AM, López-Bujanda Z, Ortiz-Quintero B, Hidalgo-Miranda A, et al. Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis. PloS one. 2014;9(12):e114104. https://doi.org/10.1371/journal.pone.0114104
https://doi.org/10.1371/journal.pone.011... ^,5757. Chen B, Yu M, Chang Q, Lu Y, Thakur C, Ma D, et al. Mdig De-Represses H19 large intergenic non-coding RNA (LincRNA) by down-regulating H3K9me3 and heterochromatin. Oncotarget . 2013;4(9):1427-37. https://doi.org/10.18632/oncotarget.1155
https://doi.org/10.18632/oncotarget.1155... ^,5858. Lu Y, Beezhold K, Chang Q, Zhang Y, Rojanasakul Y, Zhao H, et al. Lung cancer -associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3. Cell Cycle. 2009;8(13):2101-9. https://doi.org/10.4161/cc.8.13.8927
https://doi.org/10.4161/cc.8.13.8927...

Along with, overexpression of BRG1 and BRM in the cisplatin toxicity,⁵⁰50. Kothandapani A, Gopalakrishnan K, Kahali B, Reisman D, Patrick SM. Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity. ExpCell Res . 2012;318(16):1973-86. https://doi.org/10.1016/j.yexcr.2012.06.011
https://doi.org/10.1016/j.yexcr.2012.06.... or doxorubicin chemo resistance mechanisms associated with the expression of the subunits SMARCB1 and SMARCA4 (BRG1) in front to NSCLC cells.⁵¹51. Dubey R, Lebensohn AM, Bahrami-Nejad Z, Marceau C, Champion M, Gevaert O, et al. Chromatin-remodeling complex SWI/SNF controls multidrug resistance by transcriptionally regulating the drug efflux pump ABCB1. Cancer Res. 2016 ;76(19):5810-21. https://doi.org/10.1158/0008-5472.CAN-16-0716
https://doi.org/10.1158/0008-5472.CAN-16... All of that, suggesting the importance of the three main epigenetic mechanisms DNA methylation, histone code modifications and chromatin remodeling complexes in cancer progression and potential new oncological therapeutic strategies in NSCLC, all of which have been shown in table I and II.

DNA gene promoters methylation in NSCLC

Based all above-mentioned, in NSCLC cells as well NSCLC solid tumors, several epigenetic spreadable alterations-aberrations have consistently been described, highlighting genome-wide DNA hypomethylation, and gene-promoter specific sequences DNA-hypermethylation.⁵⁹59. Rauch T, Wang Z, Zhang X, Zhong X, Wu X, Lau SK, et al. Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci . 2007;104(13):5527-32. https://doi.org/10.1073/pnas.0701059104
https://doi.org/10.1073/pnas.0701059104... ^,6060. Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, et al. High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci . 2008;105(1):252-7. https://doi.org/10.1073/pnas.0710735105
https://doi.org/10.1073/pnas.0710735105...

Alterations in DNA-sequences methylation located at 5’ position in the cytosine base in a CpG dinucleotide context, develop a pathophysiological condition in cancer cells known as hypermethylated “CpG islands”, in almost all NSCLC cases, these CpG islands are located mainly in tumor suppressor genes (Eg., O⁶-methylguanine-DNA-mehtyltransferase MGMT) codifying for a DNA-repair protein, which has a pivotal role for DNA-repairing, and cellular cycle control mechanisms.⁶¹61. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415-28. https://doi.org/10.1038/nrg816
https://doi.org/10.1038/nrg816... Thus, DNA hypermethylation at specific gene promoter sequences represents an important mechanism for loss of genetic function for several NSCLC histopathological types. In accord to two-hit model from Knudson, the phenotypic consequence of loss of the tumor-suppressor gene function, is not seen unless both alleles of the tumor suppressor genes are inactivated. In NSCLC there have been described gene mutations for one genetic allele, meanwhile, an additional allele is epigenetic silenced by hypermethylation. As functionally occurs for O⁶-MGMT protein removing carcinogen-induced O⁶-methylguanine adducts, resulting in G-A transition mutations in several driver-genes, such as p53 (P53) and K-RAS, promoting malignant abilities.⁶¹61. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415-28. https://doi.org/10.1038/nrg816
https://doi.org/10.1038/nrg816... In advanced NSCLC epigenetic inactivation events by DNA methylation precede to RAS genetic alterations, as well as in lung pre-malignant lesions, with a significant impaired overall survival in NSCLC patients.⁶²62. Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nature Genet. 2000;25:315. https://doi.org/10.1038/77083
https://doi.org/10.1038/77083...

In addition, tumor suppressor genes epigenetically disrupted are often found in genome-wide regions, near of chromosomal deletions; whose genetic deletions cause loss of heterozygosity (LOH). On that epigenetic inactivation of important genes as, RASSF1A,⁶³63. Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst. 2001;93(9):691-9. https://doi.org/10.1093/jnci/93.9.691
https://doi.org/10.1093/jnci/93.9.691... and hypermethylated in cancer 1 (HIC1) gene (encoding a Zinc Finger Transcription Factor, at Chr:17p13.3) are usually inactivated by hypermethylation mechanisms in several lung malignant diseases.⁶⁴64. Wales MM, Biel MA, el Deiry W, Nelkin BD, Issa JP, Cavenee WK, et al. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med. 1995;1(6):570-7. https://doi.org/10.1038/nm0695-570
https://doi.org/10.1038/nm0695-570... Nevertheless, recently it was proposed that higher-frequency LOH regions not caused by genetic-mutation mechanism, is a principal candidate tumor-suppressor gene disability mechanism, where no-additional mutated genes have nearly been found.³⁰30. Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J, Sanchez-Cespedes M. Frequent BRG1/SMARCA4-Inactivating mutations in human lung cancer cell lines. Hum Mutat. 2008;29(5)617-22. https://doi.org/10.1002/humu.20730
https://doi.org/10.1002/humu.20730... However, 5-methylcytosine as per se known mutagenic nature, has been involved promoting tumorigenicity (G-T transversion mutations), caused by spontaneous hydrolytic deamination induced by tobacco carcinogens (benzo(a)pyrene diol epoxide), associated with tobacco consumption background in NSCLC patients.⁶⁵65. Yoon JH, Smith LE, Feng Z, Tang MS, Lee CS, Pfeifer GP. Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res. 2001;61(19):7110-7.

At least 50% of all inactivating point-mutations at coding region of the human TP53 tumor-suppressor gene, occur at methylated cytosines where methylated CpG dinucleotides increase UV-induced mutations, due that the methyl-group shifts the UV absorption spectrum for cytosine-base by the light-spectrum in sunlight exposure, affecting chemical and epigenetically gene-drivers in smokers with lung cancer.⁶¹61. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415-28. https://doi.org/10.1038/nrg816
https://doi.org/10.1038/nrg816... ^,6565. Yoon JH, Smith LE, Feng Z, Tang MS, Lee CS, Pfeifer GP. Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res. 2001;61(19):7110-7.

While, at epigenome-wide level have been identified several epigenetic aberrations in genome-loci, and/or focal DNA gene-promoters sequences as potential epigenetic biomarkers, highlighting homeobox-related (HOX) locus, known as HOX-clusters A, B, C and D encoding genes located at Chr:2, Chr:7, Chr:12 and Chr:17, epigenetically regulated by DNA methylation in both NSCLC cells and NSCLC tumors derived from stage I patients, highlighting promoter-sequences hypermethylation on HOXA7 and HOXA9 genes.⁵⁹59. Rauch T, Wang Z, Zhang X, Zhong X, Wu X, Lau SK, et al. Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci . 2007;104(13):5527-32. https://doi.org/10.1073/pnas.0701059104
https://doi.org/10.1073/pnas.0701059104... As well as, DNA hypermethylation in additional HOX encoding-gene promoters as: OTX1, OSR1, IRX2 and NR2E1 for stage I-III NSCLC patients,²⁹29. Wong AK, Shanahan F, Chen Y, Lian L, Ha P, Hendricks K, et al. BRG1, a component of the SWI-SNF complex, Is mutated in multiple human tumor cell lines. Cancer Res. 2000;60(21):6171-7. reinforcing that DNA-methylation may be used as persistent epigenetic biomarkers for basic research and clinical-stage progression of NSCLC patients.⁶⁰60. Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, et al. High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci . 2008;105(1):252-7. https://doi.org/10.1073/pnas.0710735105
https://doi.org/10.1073/pnas.0710735105... ^,6666. Rauch TA, Wang Z, Wu X, Kernstine KH, Riggs AD, Pfeifer GP. DNA methylation biomarkers for lung cancer. Tumor Biol. 2012;33(2):287-96. https://doi.org/10.1007/s13277-011-0282-2
https://doi.org/10.1007/s13277-011-0282-... Finally, resulting in a) the activation of genetic repetitive elements, b) genomic DNA-instability and c) constitutive genetic expression of specific oncogenes patterns, representing pivotal key elements involved in carcinogenic and/or tumorigenesis processes, as part of the emerging hallmarks of cancer, as genome-instability phenomena, and probably epigenome instability-variability as emerging hallmarks of NSCLC.⁶⁷67. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646-74. https://doi.org/10.1016/j.cell.2011.02.013
https://doi.org/10.1016/j.cell.2011.02.0...

Histone code modifications in NSCLC

Epigenetic (post-translational) modifications of the histone code conforming to nucleosomes are continually contributing with reversible stability into the biological processes of transcription, nuclear architecture, and genomic stability, which occur through the N-terminal domain modifications by acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP-ribosylation and deamination.⁶⁸68. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705. https://doi.org/10.1016/j.cell.2007.02.005
https://doi.org/10.1016/j.cell.2007.02.0...

On that epigenetic marks, by acetylation in lysine residues (Eg., H4K16ac) and trimethylation of the lysine 20 residue (H4K20me3), have importantly been identified as early lung epigenetic biomarkers. Importantly, loss of the differentiation-specific histone marker H3K9me3, continuously occurs in lower density CpGs regions in several types of malignant diseases, next to the gene promoter sequences known as “CpG island-shores”. Moreover, it has well been described that variation in the DNA methylation rates outside of the CpG islands, contributes directly to the NSCLC heterogenicity. Furthermore, it has been well characterized loss of the active histone marks H3K9ac and H3K4me3, with an increased enrichment of the repressive histone marks H3K27me3 and H3K9me2/me3 (figure 1), of which biological and clinically correlate with lung malignant progression, and poor therapy responses in NSCLC.¹⁶16. Balgkouranidou I, Liloglou T, Lianidou ES. Lung cancer epigenetics: emerging biomarkers. Biomark Med. 2013;7(1):49-58. https://doi.org/10.2217/bmm.12.111
https://doi.org/10.2217/bmm.12.111... ^,6969. Comer BS, Ba M, Singer CA, Gerthoffer WT. Epigenetic targets for novel therapies of lung diseases. Pharmacol Ther. 2015;147:91-110. https://doi.org/10.1016/j.pharmthera.2014.11.006
https://doi.org/10.1016/j.pharmthera.201... ^,7070. Vendetti FP, Rudin CM. Epigenetic therapy in non-small-cell lung cancer: targeting DNA methyltransferases and histone deacetylases. Expert Opin Biol Ther. 2013;13(9):1273-85. https://doi.org/10.1517/14712598.2013.819337
https://doi.org/10.1517/14712598.2013.81...

Reports have described that low levels of H3K9me2 are associated with poor prognosis in lung cancer, and other epithelial types of cancer. While low levels of H3K18ac and H3K4me2 predict poor prognosis in NSCLC patients.²¹21. Seligson DB, Horvath S, McBrian MA, Mah V, Yu H, Tze S, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol. 2009;174(5):1619-28. https://doi.org/10.2353/ajpath.2009.080874
https://doi.org/10.2353/ajpath.2009.0808... In particular, Van Den Broeck and colleagues in 2008, have identified that trimethylation state in lysine 20 of histone H4 (H4K20me3) allows the prognosis stratification of AD-NSCLC patients with higher risk of death in clinical stage I. H4K20me3 has additionally been proposed as biomarker in subgroups of AD patients with poor differential clinical prognosis, and potentially determinant for the use of adjuvant chemotherapy.⁷¹71. Van Den Broeck A, Brambilla E, Moro-Sibilot D, Lantuejoul S, Brambilla C, Eymin B, et al. Loss of histone H4K20 trimethylation occurs in preneoplasia and influences prognosis of non-small cell lung cancer. Clin Cancer Res. 2008;14(22):7237-45. https://doi.org/10.1158/1078-0432.CCR-08-0869
https://doi.org/10.1158/1078-0432.CCR-08...

Additionally, while low levels of the histone mark H3K27me3 have been associated with chemo resistance and poor prognosis in NSCLC patients,⁵⁶56. Ávila-Moreno F, Armas-López L, Álvarez-Moran AM, López-Bujanda Z, Ortiz-Quintero B, Hidalgo-Miranda A, et al. Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis. PloS one. 2014;9(12):e114104. https://doi.org/10.1371/journal.pone.0114104
https://doi.org/10.1371/journal.pone.011... additional reports have confirmed that higher expression of H3K27me3 correlates with better overall survival (OS) and better prognosis, redefining subgroups of NSCLC patients with an epigenetic phenotype and different clinical outcome.⁷²72. Chen X, Song N, Matsumoto K, Nanashima A, Nagayasu T, Hayashi T, et al. High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer. Int J Oncol. 2013;43(5):1467-80. https://doi.org/10.3892/ijo.2013.2062
https://doi.org/10.3892/ijo.2013.2062...

Additionally, despite histone marks H3K4me2, H2AK5ac and H3K9ac are related to global and disease-free survival in early clinical stages of NSCLC patients, undergoing curative surgical resection.⁷³73. Barlési F, Giaccone G, Gallegos-Ruiz MI, Loundou A, Span SW, Lefesvre P, et al. Global histone modifications predict prognosis of resected non-small-cell lung cancer. J Clin Oncol. 2007;25(28):4358-64. https://doi.org/10.1200/JCO.2007.11.2599
https://doi.org/10.1200/JCO.2007.11.2599... However, due that histone modifications are associated with tumor suppressor gene repression mechanisms or oncogene activation, the behavior of such reversible histone code modifications must be studied in a depth manner, which will be necessary for a deep understanding to define their predictive role and/or functional in the experimental or clinical management in the NSCLC progression, and new pharmaco-epigenetics therapy field on NSCLC.

Conclusions

Future directions: Integrative studies by chromatin remodeling complexes in NSCLC

Over-represented emerging epigenetic biomarkers as biomolecular signals of the malignant cellular transformation processes represent powerful molecular tools in the transitory of molecular and histological steps, in accord with early diagnosis and/or late predictive tumor aggressiveness to predict therapy responses. To date remaining functionally unknown several epigenetic complex mechanisms to support novel applied epigenetic-drugs (pharmaco-epigenetics therapy) knowledge in NSCLC.

Spite that CpGs islands, represent approximately 1% of the total of human genome, located near of, or in gene-promoter sequences, global spread epigenetic marks in NSCLC epigenome has not just commonly been associated with the genome instability, and/or aberrant genetic expression patterns in early and late events in human NSCLC tumorigenesis. Instead or in addition chromatin remodeling complexes (Trithorax, NuRD, and Polycomb complexes) are epigenetically controlling genetic sequences in an active-dependent, but in an independent well-known DNA methylation status at several driver-gene promoter sequences, in others p16, H-cadherin, RASSF1A, APC, DAPK1, EGFR, BRAF, AKT/ALK, MEOX2/GLI1, SMARCB1, etc. (figure 1). Due that aberrant DNA methylation, histone code modifications and chromatin remodeling complexes gene expression and function rates, must be, begun as useful and standard tools in NSCLC diagnosis, lung malignant histological-phenotype subtype, clinical stage, malignant aggressiveness and therapy prognosis response, as well as, probably epigenetic-biomarkers associated with the risk for lung cancer development.¹⁶16. Balgkouranidou I, Liloglou T, Lianidou ES. Lung cancer epigenetics: emerging biomarkers. Biomark Med. 2013;7(1):49-58. https://doi.org/10.2217/bmm.12.111
https://doi.org/10.2217/bmm.12.111...

However, to date relevant knowledge about higher molecular complexity of the epigenetic mechanisms, must be considered, but based on the several new molecular alterations of the well-assembled mechanisms of the Chromatin Remodeling Complexes, such as: Trithorax (SMARCB1, SMARCA2, SMARCA4, etc.), NuRD (RBBP7, MTA2, HDAC1, etc.), and Polycomb (EZH2, BMI-1, etc.) complexes (figure 1). Some of which have been clinically and oncologically validated on in vitro experimental NSCLC cellular and in vivo models, and implicated in NSCLC patients, described and summarized in table I. Which, in the advanced therapeutically strategies must be functional analyzed in synchronicity with the nucleosome structures and histone-code patterns on the functional epigenome-occupancy, whose biological and clinical implications in human NSCLC, have previously been reported, and summarized in table II. All of that, must be deeply studied, for a better and integral epigenetic-knowledge (DNA methylation, histone modifications and remodeling complexes patterns) into the control mechanisms of transcriptional regulations status, helpful to explain genetic-epigenetic cancer biomarkers expression (figure 1), all necessary for future concerns in lung cancer biology, personalized medicine, and emerging hallmarks of cancer applied into the translational medicine, accompanied by imaging technologies for diagnosis, and prognosis in NSCLC oncological therapies.

Acknowledgments

We would like to thank to the Postdoctoral Fellowship Program by DGAPA-UNAM, assigned to Dr. Irlanda Peralta Arrieta at FES-Iztacala, UBIMED. Thanks to pre-grade students Priscila Pineda-Villegas, Carmen Ordoñez-Luna and Nallely Hernández-Cigala by the enthusiastic academic discussion during manuscript writing. Additionally, to thank to the grant support projects PAPIIT-DGAPA: IN226317 from the Universidad Nacional Atónoma de México (UNAM), and FOSISS 2016-1: 00272655 from the Consejo Nacional de Ciencia y Tecnología (Conacyt). Finally, to the inter-institutional collaboration agreement UNAM-INER, with a register number: UNAM 43355-3065-17-XI-15.

References

Publication Dates

History