Yıl: 2019 Cilt: 43 Sayı: 3 Sayfa Aralığı: 155 - 170 Metin Dili: İngilizce DOI: 10.3906/biy-1903-39 İndeks Tarihi: 11-05-2020

Key actors in cancer therapy: epigenetic modifiers

Öz:
Epigenetic reprogramming plays a crucial role in the tumorigenicity and maintenance of tumor-specific gene expression thatespecially occurs through DNA methylation and/or histone modifications. It has well-defined mechanisms. It is known that alterationsin the DNA methylation pattern and/or the loss of specific histone acetylation/methylation markers are related to several hallmarks ofcancer, such as drug resistance, stemness, epithelial–mesenchymal transition, and metastasis. It has also recently been highlighted thatepigenetic alterations are critical for the regulation of the stemlike properties of cancer cells (tumor-initiating cells; cancer stem cells).Cancer stem cells are thought to be responsible for the recurrence of cancer which makes the patient return to the clinic with metastatictumor tissue. Hence, the dysregulation of epigenetic machinery represents potential new therapeutic targets. Therefore, compounds withepigenetic activities have become crucial for developing new therapy regimens (e.g., antimetastatic agents) in the fight against cancer.Here, we review the epigenetic modifiers that have already been used in the clinic and/or in clinical trials, related preclinical studies incancer therapy, and the smart combination strategies that target cancer stem cells along with the other cancer cells. The emerging role ofepitranscriptome (RNA epigenetic) in cancer therapy has also been included in this review as a new avenue and potential target for thebetter management of cancer-beneficial epigenetic machinery
Anahtar Kelime:

Konular: Biyoloji
Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
  • Annunziato A (2008). DNA packaging: nucleosomes and chromatin. Nature Education 1 (1): 26.
  • Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M et al. (2014). Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510 (7504): 278-282.
  • Azad N S, El-Khoueiry A, Yin J, Oberg AL, Flynn P et al. (2017). Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand up 2 cancer study. Oncotarget 8 (21): 35326.
  • Aztopal N, Erkisa M, Ari F, Dere E, Ulukaya E (2018a). Dual inhibition of Wnt/beta-catenin signaling and histone deacetylation as a new strategy to eliminate breast cancer stem cells by augmentation of apoptosis. In FEBS Open Bio (Vol. 8). Hoboken, NJ, USA: Wiley. pp. 301-301.
  • Aztopal N, Erkisa M, Erturk E, Ulukaya E, Tokullugil AH, Ari F (2018b). Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells. Chemico-Biological Interactions 280: 51-58.
  • Baba T, Convery PA, Matsumura N, Whitaker RS, Kondoh E et al. (2009). Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 28 (2): 209-218.
  • Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O et al. (2006). EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. Journal of Clinical Oncology 24 (2): 268-273.
  • Bannister AJ, Kouzarides T (2011). Regulation of chromatin by histone modifications. Cell Research 21 (3): 381-395. Baylin SB (2005). DNA methylation and gene silencing in cancer. Nature Reviews Clinical Oncology 2 (S1), S4.
  • Bernstein BE, Meissner A, Lander ES (2007). The mammalian epigenome. Cell 128 (4): 669-681.
  • Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ et al. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125 (2): 315-326.
  • Bird A (2002). DNA methylation patterns and epigenetic memory. Genes & Development 16 (1): 6-21.
  • Blumenschein GR, Kies MS, Papadimitrakopoulou VA, Lu C, Kumar AJ et al. (2008). Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Investigational New Drugs 26 (1): 81-87.
  • Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K (2006). Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes & Development 20 (9): 1123-1136.
  • Braiteh F, Soriano AO, Garcia-Manero G, Hong D, Johnson MM et al. (2008). Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clinical Cancer Research 14 (19): 6296-6301.
  • Brueckner B, Boy RG, Siedlecki P, Musch T, Kliem HC et al. (2005). Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Research 65 (14): 6305-6311.
  • Budden T, van der Westhuizen A, Bowden NA (2018). Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma. BMC Cancer 18 (1): 100.
  • Burke MJ, Lamba JK, Pounds S, Cao X, Ghodke‐Puranik Y et al. (2014). A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia. American Journal of Hematology 89 (9): 889-895.
  • Catalano MG, Poli R, Pugliese M, Fortunati N, Boccuzzi G (2007). Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines. Endocrine-Related Cancer 14 (3): 839-845.
  • Chen CL, Sung J, Cohen M, Chowdhury WH, Sachs MD et al. (2006). Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. Journal of Pharmacology and Experimental Therapeutics 319 (2): 533-542.
  • Chen Y, Wang XQ, Zhang Q, Zhu JY, Li Y et al. (2017). (−)-Epigallocatechin-3-gallate inhibits colorectal cancer stem cells by suppressing wnt/β-catenin pathway. Nutrients 9 (6): 572.
  • Chikamatsu K, Ishii H, Murata T, Sakakura K, Shino M et al. (2013). Alteration of cancer stem cell‐like phenotype by histone deacetylase inhibitors in squamous cell carcinoma of the head and neck. Cancer Science 104 (11): 1468-1475.
  • Christman JK (2002). 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21 (35): 5483-5495.
  • Chung SS, Vadgama JV (2015). Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via downregulation of STAT3–NFκB signaling. Anticancer Research 35 (1): 39-46.
  • Cipro Š, Hřebačková J, Hraběta J, Poljaková J, Eckschlager T (2012). Valproic acid overcomes hypoxia-induced resistance to apoptosis. Oncology Reports 27 (4): 1219-1226.
  • Clermont PL, Fornaro L, Crea F (2017). Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer. Epigenomics 9 (10): 1329-1335.
  • Cui Q, Shi H, Ye P, Li L, Qu Q et al. (2017). m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Reports 18 (11): 2622-2634.
  • da Motta LL, Ledaki I, Purshouse K, Haider S, De Bastiani MA et al. (2017). The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene 36 (1): 122-132.
  • Desrosiers R, Friderici K, Rottman F (1974). Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proceedings of the National Academy of Sciences 71 (10): 3971-3975.
  • Easwaran H, Tsai HC, Baylin SB (2014). Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Molecular Cell 54 (5): 716-727.
  • Eckschlager T, Plch J, Stiborova M, Hrabeta J (2017). Histone deacetylase inhibitors as anticancer drugs. International Journal of Molecular Sciences 18 (7): 1414.
  • Falkenberg KJ, Johnstone RW (2014). Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nature Reviews Drug Discovery 13 (9): 673-691.
  • Fang F, Balch C, Schilder J, Breen T, Zhang S et al. (2010). A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum‐resistant, epithelial ovarian cancer. Cancer 116 (17): 4043-4053.
  • Fang F, Munck J, Tang J, Taverna P, Wang Y et al. (2014). The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clinical Cancer Research 20 (24): 6504-6516.
  • Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB et al. (2010). Selective inhibition of BET bromodomains. Nature 468 (7327): 1067-1073.
  • Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J et al. (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genetics 37 (4): 391-400.
  • Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S et al. (2013). RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell, 155 (4): 793-806.
  • Gailhouste L, Liew LC, Hatada I, Nakagama H, Ochiya T (2018). Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells. Cell Death & Disease 9 (5): 468.
  • Gerber DE, Boothman DA, Fattah FJ, Dong Y, Zhu H et al. (2015). Phase 1 study of romidepsin plus erlotinib in advanced nonsmall cell lung cancer. Lung Cancer 90 (3): 534-541.
  • Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N et al. (2015). m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 347 (6225): 1002-1006.
  • Grabarska A, Łuszczki JJ, Nowosadzka E, Gumbarewicz E, Jeleniewicz W et al. (2017). Histone deacetylase inhibitor SAHA as potential targeted therapy agent for larynx cancer cells. Journal of Cancer 8 (1): 19-28.
  • Guo Y, Shu L, Zhang C, Su ZY, Kong ANT (2015). Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1. Biochemical Pharmacology 94 (2): 69-78.
  • Haberland M, Montgomery RL, Olson EN (2009). The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Reviews Genetics 10 (1): 32-42.
  • Haigentz Jr M, Kim M, Sarta C, Lin J, Keresztes RS et al. (2012). Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. Oral Oncology 48 (12): 1281-1288.
  • Halkidou K, Gaughan L, Cook S, Leung HY, Neal DE et al. (2004). Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. The Prostate 59 (2): 177-189.
  • Hayashi A, Horiuchi A, Kikuchi N, Hayashi T, Fuseya C et al. (2010). Type‐specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E‐cadherin. International Journal of Cancer 127 (6): 1332-1346.
  • Herceg Z (2007). Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. Mutagenesis 22 (2): 91-103.
  • Hosokawa M, Tanaka S, Ueda K, Iwakawa S (2017). Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells. Biological and Pharmaceutical Bulletin: b17-00439.
  • Ikeda JI, Morii E, Kimura H, Tomita Y, Takakuwa T et al. (2006). Epigenetic regulation of the expression of the novel stem cell marker CDCP1 in cancer cells. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland 210 (1): 75-84.
  • Issa JPJ, Kantarjian HM (2009). Targeting DNA methylation. Clinical Cancer Research 15 (12): 3938-3946.
  • James MI, Iwuji C, Irving G, Karmokar A, Higgins JA (2015). Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Letters 364 (2): 135-141.
  • Jenuwein T, Allis CD (2001). Translating the histone code. Science 293 (5532): 1074-1080.
  • Jiang P, Xu C, Chen L, Chen A, Wu X et al. (2018). Epigallocatechin‐3‐ gallate inhibited cancer stem cell–like properties by targeting hsa‐mir‐485‐5p/RXRα in lung cancer. Journal of Cellular Biochemistry 119 (10): 8623-8635.
  • Jones PA, Baylin SB (2007). The epigenomics of cancer. Cell 128 (4): 683-692. Jones PA, Issa JPJ, Baylin S (2016). Targeting the cancer epigenome for therapy. Nature Reviews Genetics 17 (10): 630-641.
  • Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M et al. (2011). Combination epigenetic therapy has efficacy in patients with refractory advanced non–small cell lung cancer. Cancer Discovery 1 (7): 598-607.
  • Juo YY, Gong XJ, Mishra A, Cui X, Baylin SB et al. (2015). Epigenetic therapy for solid tumors: from bench science to clinical trials. Epigenomics 7 (2): 215-235.
  • Kagara N, Huynh KT, Kuo C, Okano H, Sim MS et al. (2012). Epigenetic regulation of cancer stem cell genes in triplenegative breast cancer. The American Journal of Pathology 181 (1): 257-267.
  • Kantarjian H, Issa JPJ, Rosenfeld CS, Bennett JM, Albitar M et al. (2006). Decitabine improves patient outcomes in myelodysplastic syndromes. Cancer 106 (8): 1794-1803.
  • Kemp CD, Rao M, Xi S, Inchauste S, Mani H et al. (2012). Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clinical Cancer Research 18 (1): 77-90.
  • Khan GN, Kim EJ, Shin TS, Lee SH (2017). Azacytidine-induced chemosensitivity to doxorubicin in human breast cancer MCF7 Cells. Anticancer Research 37 (5): 2355-2364.
  • Kim SJ, Amankwah E, Connors S, Park HY, Rincon M et al. (2014). Safety and chemopreventive effect of Polyphenon E in preventing early and metastatic progression of prostate cancer in TRAMP mice. Cancer Prevention Research 7 (4): 435-444.
  • Kleer CG, Cao Q, Varambally S, Shen R, Ota I et al. (2003). EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proceedings of the National Academy of Sciences 100 (20): 11606-11611.
  • Klose RJ, Bird AP (2006). Genomic DNA methylation: the mark and its mediators. Trends in Biochemical Sciences 31 (2): 89-97.
  • Kondo Y, Shen L, Ahmed S, Boumber Y, Sekido Y et al. (2008). Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PloS One 3 (4): e2037.
  • Kornblith AB, Herndon JE, Silverman LR, Demakos EP, OdchimarReissig R et al. (2002). Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. Journal of Clinical Oncology 20 (10): 2441-2452.
  • Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S et al. (2015). A phase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. International Journal of Radiation Oncology* Biology* Physics 92 (5): 986-992.
  • Kuang Y, El-Khoueiry A, Taverna P, Ljungman M, Neamati N (2015). Guadecitabine (SGI‐110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin. Molecular Oncology 9 (9): 1799- 1814.
  • Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B et al. (2005). Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Annals of Hematology 84 (1): 61-66.
  • Leal AS, Williams CR, Royce DB, Pioli PA, Sporn MB et al. (2017). Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer. Cancer Letters 394: 76-87.
  • Lee DH, Qi J, Bradner JE, Said JW, Doan NB (2015a). Synergistic effect of JQ 1 and rapamycin for treatment of human osteosarcoma. International Journal of Cancer 136 (9): 2055-2064.
  • Lee TG, Jeong EH, Kim SY, Kim HR, Kim CH (2015b). The combination of irreversible EGFR TKI s and SAHA induces apoptosis and autophagy‐mediated cell death to overcome acquired resistance in EGFR T 790 M‐mutated lung cancer. International Journal of Cancer 136 (11): 2717-2729.
  • Lee WY, Chen PC, Wu WS, Wu HC, Lan CH et al. (2017). Panobinostat sensitizes KRAS‐mutant non‐small‐cell lung cancer to gefitinib by targeting TAZ. International Journal of Cancer 141 (9): 1921-1931.
  • Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RWC et al. (2014). Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5 (3): 587-598.
  • Li LH, Zhang PR, Cai PY, Li C (2016). Histone deacetylase inhibitor, Romidepsin (FK228) inhibits endometrial cancer cell growth through augmentation of p53-p21 pathway. Biomedicine & Pharmacotherapy 82: 161-166.
  • Li SY, Sun R, Wang HX, Shen S, Liu Y et al. (2015). Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells. Journal of Controlled Release 205: 7-14.
  • Li X, Tang J, Huang W, Wang F, Li P et al. (2017). The M6A methyltransferase METTL3: acting as a tumor suppressor in renal cell carcinoma. Oncotarget 8 (56): 96103-96116.
  • Li Z, Wang Y, Qiu J, Li Q, Yuan C et al. (2013). The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer. Oncotarget 4 (12): 2532-2549.
  • Liu CC, Lin JH, Hsu TW, Su K, Li AFY et al. (2015). IL‐6 enriched lung cancer stem‐like cell population by inhibition of cell cycle regulators via DNMT1 upregulation. International Journal of Cancer 136 (3): 547-559.
  • Liu Z, Xie Z, Jones W, Pavlovicz RE, Liu S et al. (2009). Curcumin is a potent DNA hypomethylation agent. Bioorganic & Medicinal Chemistry Letters 19 (3): 706-709.
  • Luchenko VL, Salcido CD, Zhang Y, Agama K, Komlodi-Pasztor E et al. (2011). Schedule-dependent synergy of histone deacetylase inhibitors with DNA damaging agents in small cell lung cancer. Cell Cycle 10 (18): 3119-3128.
  • Luu TH, Morgan RJ, Leong L, Lim D, McNamara M et al. (2008). A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clinical Cancer Research 14 (21): 7138-7142.
  • Matei D, Fang F, Shen C, Schilder J, Arnold A et al. (2012). Epigenetic resensitization to platinum in ovarian cancer. Cancer Research 72 (9): 2197-2205.
  • Medeiros BC, McCaul K, Kambhampati S, Pollyea DA, Kumar R et al. (2018). Randomized study of continuous high-dose lenalidomide, sequential azacitidine and lenalidomide, or azacitidine in persons 65 years and over with newly-diagnosed acute myeloid leukemia. Haematologica 103 (1): 101-106.
  • Meissner A (2010). Epigenetic modifications in pluripotent and differentiated cells. Nature Biotechnology 28 (10): 1079-1088.
  • Min A, Im SA, Kim DK, Song SH, Kim HJ et al. (2015). Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells. Breast Cancer Research 17 (1): 33.
  • Modesitt SC, Sill M, Hoffman JS, Bender DP (2008). A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecologic Oncology 109 (2): 182-186.
  • Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Andtbacka RH et al. (2006). Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Research 66 (7): 3773-3781.
  • Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC et al. (2002). Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Research 62 (22): 6456- 6461.
  • Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K et al. (2018). Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer. Oncotarget 9 (7): 7476-7486.
  • Noguchi H, Yamashita H, Murakami T, Hirai K, Noguchi Y et al. (2008). Successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy, radiation and surgery. Endocrine Journal: 0812020217- 0812020217. 245-249
  • Noh JH, Eun JW, Ryu SY, Jeong KW, Kim JK et al. (2006). Increased expression of histone deacetylase 2 is found in human hepatocellular carcinoma. Molecular and Cellular Toxicology 2 (3): 166-169.
  • O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P et al. (2015). Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. Journal of Clinical Oncology 33 (23): 2492-2499
  • O’Connor OA, Özcan M, Jacobsen ED, Vidal JMR, Trotman J et al. (2015). First multicenter, randomized phase 3 study in patients (Pts) with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL): Alisertib (MLN8237) versus investigator’s choice (Lumiere trial; NCT01482962). Blood 126 (23): 341. 12-13
  • Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM et al. (2007). Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. Journal of Clinical Oncology 25 (21): 3109- 3115.
  • Ong PS, Wang L, Chia DMH, Seah JYX, Kong LR et al. (2016). A novel combinatorial strategy using Seliciclib® and Belinostat® for eradication of non-small cell lung cancer via apoptosis induction and BID activation. Cancer Letters 381 (1): 49-57.
  • Pérez-Salvia M, Esteller M (2017). Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics 12 (5): 323-339.
  • Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL et al. (2009). Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. Journal of Clinical Oncology 27 (32): 5410-5417.
  • Popis MC, Blanco S, Frye M (2016). Post-transcriptional methylation of transfer and ribosomal RNA in stress response pathways, cell differentiation and cancer. Current Opinion in Oncology 28 (1): 65-71.
  • Qian X, Ara G, Mills E, LaRochelle WJ, Lichenstein HS et al. (2008). Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. International Journal of Cancer 122 (6): 1400-1410.
  • Raffoux E, Cras A, Recher C, Boëlle PY, de Labarthe A et al. (2010). Phase 2 clinical trial of 5-azacitidine, valproic acid, and alltrans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget 1(1): 34- 42.
  • Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA et al. (2016). Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood 127 (6): 713-721.
  • Saletore Y, Meyer K, Korlach J, Vilfan ID, Jaffrey S, Mason CE (2012). The birth of the Epitranscriptome: deciphering the function of RNA modifications. Genome Biology 13 (10): 175. doi: 10.1186/gb-2012-13-10-175
  • Samavat H, Newman AR, Wang R, Yuan JM, Wu AH et al. (2016). Effects of green tea catechin extract on serum lipids in postmenopausal women: a randomized, placebo-controlled clinical trial. The American Journal of Clinical Nutrition 104 (6): 1671-1682.
  • San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA et al. (2014). Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. The Lancet Oncology 15 (11): 1195-1206.
  • San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA et al. (2016). Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. The Lancet Haematology 3 (11): e506-e515.
  • Sato T, Issa JPJ, Kropf P (2017). DNA hypomethylating drugs in cancer therapy. Cold Spring Harbor Perspectives in Medicine 7 (5): a026948. doi: 10.1101/cshperspect.a026948.
  • Sawada G, Takahashi Y, Niida A, Shimamura T, Kurashige J et al. (2014). Loss of CDCP1 expression promotes invasiveness and poor prognosis in esophageal squamous cell carcinoma. Annals of Surgical Oncology 21 (4): 640-647.
  • Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F et al. (2010). A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141 (1): 69-80.
  • Sherman EJ, Su YB, Lyall A, Schöder H, Fury MG et al. (2013). Evaluation of romidepsin for clinical activity and radioactive iodine reuptake in radioactive iodine–refractory thyroid carcinoma. Thyroid 23 (5): 593-599.
  • Shi J, Wang E, Zuber J, Rappaport A, Taylor M et al. (2013). The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9; Nras G12D acute myeloid leukemia. Oncogene 32 (7): 930-938.
  • Shi Y (2007). Histone lysine demethylases: emerging roles in development, physiology and disease. Nature Reviews Genetics 8 (11): 829-833.
  • Simon JA, Lange CA (2008). Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 647 (1-2): 21-29.
  • Srivastava P, Paluch BE, Matsuzaki J, James SR, Collamat-Lai G et al. (2015). Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics 10 (3): 237-246.
  • Steele N, Finn P, Brown R, Plumb JA (2009). Combined inhibition of DNA methylation and histone acetylation enhances gene reexpression and drug sensitivity in vivo. British Journal of Cancer 100 (5): 758-763.
  • Stockhausen MT, Sjölund J, Manetopoulos C, Axelson H (2005). Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells. British Journal of Cancer 92 (4): 751-759.
  • Sulaiman A, Sulaiman B, Khouri L, McGarry S, Nessim C et al. (2016). Both bulk and cancer stem cell subpopulations in triple‐ negative breast cancer are susceptible to Wnt, HDAC, and ERα coinhibition. FEBS Letters 590 (24): 4606-4616.
  • Suvà ML, Riggi N, Janiszewska M, Radovanovic I, Provero P et al. (2009). EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Research 69 (24): 9211-9218.
  • Tabu K, Sasai K, Kimura T, Wang L, Aoyanagi E et al. (2008). Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Research 18 (10): 1037-1046.
  • Takashina T, Kinoshita I, Kikuchi J, Shimizu Y, Sakakibara‐Konishi J et al. (2016). Combined inhibition of EZH 2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells. Cancer Science 107 (7): 955-962.
  • Tammen SA, Friso S, Choi SW (2013). Epigenetics: the link between nature and nurture. Molecular Aspects of Medicine 34 (4): 753- 764.
  • Tate CR, Rhodes LV, Segar HC, Driver JL, Pounder FN et al. (2012). Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat. Breast Cancer Research 14(3): R79. doi: 10.1186/bcr3192
  • Thaler F (2012). Current trends in the development of histone deacetylase inhibitors: a review of recent patent applications. Pharmaceutical Patent Analyst 1 (1): 75-90.
  • Thomas A, Rajan A, Szabo E, Tomita Y, Carter CA et al. (2014). A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study. Clinical Cancer Research 20 (21): 5392-5402.
  • Tian J, Lee SO, Liang L, Luo J, Huang CK et al. (2012). Targeting the unique methylation pattern of androgen receptor (AR) promoter in prostate stem/progenitor cells with 5-aza2′-deoxycytidine (5-AZA) leads to suppressed prostate tumorigenesis. Journal of Biological Chemistry 287 (47): 39954-39966.
  • Toden S, Tran HM, Tovar-Camargo OA, Okugawa Y, Goel A (2016). Epigallocatechin-3-gallate targets cancer stem-like cells and enhances 5-fluorouracil chemosensitivity in colorectal cancer. Oncotarget 7 (13): 16158-16171.
  • Toh TB, Lim JJ, Chow EKH (2017). Epigenetics in cancer stem cells. Molecular Cancer 16 (1): 29. doi: 10.1186/s12943-017-0596- 9. Traynor AM, Dubey S, Eickhoff JC, Kolesar JM, Schell K et al. (2009). Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. Journal of Thoracic Oncology 4 (4): 522-526.
  • Tsai HC, Li H, Van Neste L, Cai Y, Robert C et al. (2012). Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21 (3): 430-446.
  • Valentini A, Gravina P, Federici G, Bernardini S (2007). Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. Cancer Biology & Therapy 6 (2): 185-191.
  • Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M (2004). Stem cells and cancer: the polycomb connection. Cell 118 (4): 409- 418.
  • van Vlerken LE, Kiefer CM, Morehouse C, Li Y, Groves C et al. (2013). EZH2 is required for breast and pancreatic cancer stem cell maintenance and can be used as a functional cancer stem cell reporter. Stem Cells Translational Medicine 2 (1): 43-52.
  • Vansteenkiste J, Van Cutsem E, Dumez H, Chen C, Ricker JL et al. (2008). Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Investigational New Drugs 26 (5): 483-488.
  • Vedeld HM, Skotheim RI, Lothe RA, Lind GE (2014). The recently suggested intestinal cancer stem cell marker DCLK1 is an epigenetic biomarker for colorectal cancer. Epigenetics 9 (3): 346-350.
  • Verma M, Kumar V (2018). Epigenetic drugs for cancer and precision medicine. In: Moskalev AA, Alexander Vaiserman A. Epigenetics of Aging and Longevity. New York/London: Academic Press, pp. 439-451.
  • Vijayaraghavalu S, Dermawan JK, Cheriyath V, Labhasetwar V (2012). Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest. Molecular Pharmaceutics 10 (1): 337-352.
  • Viré E, Brenner C, Deplus R, Blanchon L, Fraga M et al. (2006). The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439 (7078): 871-874.
  • Von Hoff DD, Rasco DW, Heath EI, Munster PN, Schellens JH et al. (2018). Phase I study of CC-486 alone and in combination with carboplatin or nab-paclitaxel in patients with relapsed or refractory solid tumors. Clinical Cancer Research 24 (17): 4072- 4080.
  • Wang X, Zhao H, Lv L, Bao L, Wang X et al. (2016). Prognostic significance of EZH2 expression in non-small cell lung cancer: A meta-analysis. Scientific Reports 6: 19239. Wang Y, Cardenas H, Fang F, Condello S, Taverna P et al. (2014).
  • Epigenetic targeting of ovarian cancer stem cells. Cancer Research 74 (17): 4922-4936.
  • Wei JW, Huang K, Yang C, Kang CS (2017). Non-coding RNAs as regulators in epigenetics. Oncology Reports 37 (1): 3-9. Weikert S, Christoph F, Köllermann J, Müller M, Schrader M et al. (2005). Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. International Journal of Molecular Medicine 16 (2): 349-353.
  • Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A et al. (2010). Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 28 (29): 4485-4491.
  • Yamashita AS, da Costa Rosa M, Borodovsky A, Festuccia WT, Chan T et al. (2018). Demethylation and epigenetic modification with 5-azacytidine reduces IDH1 mutant glioma growth in combination with temozolomide. Neuro-Oncology 21 (2): 189- 200.
  • Yi JM, Tsai HC, Glöckner SC, Lin S, Ohm JE et al. (2008). Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Research 68 (19): 8094-8103.
  • You H, Ding W, Rountree CB (2010). Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor‐β. Hepatology 51 (5): 1635-1644.
  • Zhang C, Samanta D, Lu H, Bullen JW, Zhang H et al. (2016). Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proceedings of the National Academy of Sciences 113 (14): E2047-E2056.
  • Zhang S, Zhao BS, Zhou A, Lin K, Zheng S et al. (2017). m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 31 (4): 591-606.
  • Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y et al. (2005). Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast. Breast Cancer Research and Treatment 94 (1): 11-16.
  • Zhao BS, Roundtree IA, He C (2017). Post-transcriptional gene regulation by mRNA modifications. Nature Reviews Molecular Cell Biology 18 (1): 31-42.
  • Zhou Y, Perez RE, Duan L, Maki CG (2018). DZNep represses Bcl-2 expression and modulates apoptosis sensitivity in response to Nutlin-3a. Cancer Biology & Therapy 19 (6): 465-474.
  • Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG et al. (2016). BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Reports 16 (11): 2829-2837.
  • Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP et al. (2004). Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5 (5): 455-463.
APA AKAR R, SELVİ S, ULUKAYA E, AZTOPAL N (2019). Key actors in cancer therapy: epigenetic modifiers. , 155 - 170. 10.3906/biy-1903-39
Chicago AKAR Remzi Okan,SELVİ Selin,ULUKAYA Engin,AZTOPAL Nazlıhan Key actors in cancer therapy: epigenetic modifiers. (2019): 155 - 170. 10.3906/biy-1903-39
MLA AKAR Remzi Okan,SELVİ Selin,ULUKAYA Engin,AZTOPAL Nazlıhan Key actors in cancer therapy: epigenetic modifiers. , 2019, ss.155 - 170. 10.3906/biy-1903-39
AMA AKAR R,SELVİ S,ULUKAYA E,AZTOPAL N Key actors in cancer therapy: epigenetic modifiers. . 2019; 155 - 170. 10.3906/biy-1903-39
Vancouver AKAR R,SELVİ S,ULUKAYA E,AZTOPAL N Key actors in cancer therapy: epigenetic modifiers. . 2019; 155 - 170. 10.3906/biy-1903-39
IEEE AKAR R,SELVİ S,ULUKAYA E,AZTOPAL N "Key actors in cancer therapy: epigenetic modifiers." , ss.155 - 170, 2019. 10.3906/biy-1903-39
ISNAD AKAR, Remzi Okan vd. "Key actors in cancer therapy: epigenetic modifiers". (2019), 155-170. https://doi.org/10.3906/biy-1903-39
APA AKAR R, SELVİ S, ULUKAYA E, AZTOPAL N (2019). Key actors in cancer therapy: epigenetic modifiers. Turkish Journal of Biology, 43(3), 155 - 170. 10.3906/biy-1903-39
Chicago AKAR Remzi Okan,SELVİ Selin,ULUKAYA Engin,AZTOPAL Nazlıhan Key actors in cancer therapy: epigenetic modifiers. Turkish Journal of Biology 43, no.3 (2019): 155 - 170. 10.3906/biy-1903-39
MLA AKAR Remzi Okan,SELVİ Selin,ULUKAYA Engin,AZTOPAL Nazlıhan Key actors in cancer therapy: epigenetic modifiers. Turkish Journal of Biology, vol.43, no.3, 2019, ss.155 - 170. 10.3906/biy-1903-39
AMA AKAR R,SELVİ S,ULUKAYA E,AZTOPAL N Key actors in cancer therapy: epigenetic modifiers. Turkish Journal of Biology. 2019; 43(3): 155 - 170. 10.3906/biy-1903-39
Vancouver AKAR R,SELVİ S,ULUKAYA E,AZTOPAL N Key actors in cancer therapy: epigenetic modifiers. Turkish Journal of Biology. 2019; 43(3): 155 - 170. 10.3906/biy-1903-39
IEEE AKAR R,SELVİ S,ULUKAYA E,AZTOPAL N "Key actors in cancer therapy: epigenetic modifiers." Turkish Journal of Biology, 43, ss.155 - 170, 2019. 10.3906/biy-1903-39
ISNAD AKAR, Remzi Okan vd. "Key actors in cancer therapy: epigenetic modifiers". Turkish Journal of Biology 43/3 (2019), 155-170. https://doi.org/10.3906/biy-1903-39