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DOI: 10.1055/s-0042-1748188
Involvement of Epigenomic Factors in Bile Duct Cancer
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Abstract
Cholangiocarcinoma (CCA) is the second most common type of primary liver cancer. Due to its often-silent manifestation, sporadic nature, and typically late clinical presentation, it remains difficult to diagnose and lacks effective nonsurgical therapeutic options. Extensive research aiming in understanding the mechanisms underlying this disease have provided strong evidence for the significance of epigenetics contributing to its onset, progression, and dissemination. This dysregulation in a myriad of signaling pathways, leading to malignancy, spans altered deoxyribonucleic acid and histone methylation, histone acetylation, and chromatin remodeling, as well as genetic modifications in essential genes controlling these epigenetic processes. An advantage to epigenetic modifications is that they, compared with mutations, are reversible and can partially be controlled by inhibiting the responsible enzymatic machinery. This opens novel possibilities for developing new treatment modalities with benefit for CCA patients.
In this article, we have reviewed the current status of epigenome modifications described in CCA, including the role of posttranslational histone modifications and chromatin remodeling, as well as novel advances in treatment options.
Keywords
epigenetics - histone modifications - DNA methylation - IDH - epigenetic therapy - biliary tract cancer - cholangiocarcinoma - CCAFinancial Support
The laboratory of JBA is supported by competitive funding from the Novo Nordisk Foundation (14040, 0058419), Danish Cancer Society (R167-A10784, R278-A16638), NEYE foundation, and the Danish Medical Research Council (1030–00070B).
Publication History
Article published online:
23 June 2022
© 2022. Thieme. All rights reserved.
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References
- 1 Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383 (9935): 2168-2179
- 2 Weigt J, Malfertheiner P. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. Expert Rev Gastroenterol Hepatol 2010; 4 (04) 395-397
- 3 Lamarca A, Palmer DH, Wasan HS. et al; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 2021; 22 (05) 690-701
- 4 Prueksapanich P, Piyachaturawat P, Aumpansub P, Ridtitid W, Chaiteerakij R, Rerknimitr R. Liver fluke-associated biliary tract cancer. Gut Liver 2018; 12 (03) 236-245
- 5 Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74 (11) 2913-2921
- 6 Chapman MH, Webster GJM, Bannoo S, Johnson GJ, Wittmann J, Pereira SP. Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis: a 25-year single-centre experience. Eur J Gastroenterol Hepatol 2012; 24 (09) 1051-1058
- 7 Schrumpf E, Boberg KM. Hepatic and extrahepatic malignancies and primary sclerosing cholangitis. Gut 2003; 52 (02) 165
- 8 Yao KJ, Jabbour S, Parekh N, Lin Y, Moss RA. Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database. BMC Gastroenterol 2016; 16 (01) 117
- 9 O'Rourke CJ, Lafuente-Barquero J, Andersen JB. Epigenome remodeling in cholangiocarcinoma. Trends Cancer 2019; 5 (06) 335-350
- 10 Høgdall D, O'Rourke CJ, Dehlendorff C. et al. Serum IL6 as a prognostic biomarker and IL6R as a therapeutic target in biliary tract cancers. Clin Cancer Res 2020; 26 (21) 5655-5667
- 11 Wehbe H, Henson R, Meng F, Mize-Berge J, Patel T. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res 2006; 66 (21) 10517-10524
- 12 Banales JM, Marin JJG, Lamarca A. et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17 (09) 557-588
- 13 Jusakul A, Cutcutache I, Yong CH. et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov 2017; 7 (10) 1116-1135
- 14 Nepal C, O'Rourke CJ, Oliveira DVNP. et al. Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology 2018; 68 (03) 949-963
- 15 Goeppert B, Konermann C, Schmidt CR. et al. Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway. Hepatology 2014; 59 (02) 544-554
- 16 Kim M, Costello J. DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med 2017; 49 (04) e322
- 17 Cheishvili D, Boureau L, Szyf M. DNA demethylation and invasive cancer: implications for therapeutics. Br J Pharmacol 2015; 172 (11) 2705-2715
- 18 Gao Y, Yang M, Jiang Z. et al. IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma. Hum Pathol 2014; 45 (06) 1184-1191
- 19 Tozawa T, Tamura G, Honda T. et al. Promoter hypermethylation of DAP-kinase is associated with poor survival in primary biliary tract carcinoma patients. Cancer Sci 2004; 95 (09) 736-740
- 20 Wong N, Li L, Tsang K, Lai PBS, To KF, Johnson PJ. Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma. J Hepatol 2002; 37 (05) 633-639
- 21 Chinnasri P, Pairojkul C, Jearanaikoon P. et al. Preferentially different mechanisms of inactivation of 9p21 gene cluster in liver fluke-related cholangiocarcinoma. Hum Pathol 2009; 40 (06) 817-826
- 22 Yang B, House MG, Guo M, Herman JG, Clark DP. Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma. Mod Pathol 2005; 18 (03) 412-420
- 23 Limpaiboon T, Khaenam P, Chinnasri P. et al. Promoter hypermethylation is a major event of hMLH1 gene inactivation in liver fluke related cholangiocarcinoma. Cancer Lett 2005; 217 (02) 213-219
- 24 Lee S, Kim WH, Jung HY, Yang MH, Kang GH. Aberrant CpG island methylation of multiple genes in intrahepatic cholangiocarcinoma. Am J Pathol 2002; 161 (03) 1015-1022
- 25 Tischoff I, Wittekind C, Tannapfel A. Role of epigenetic alterations in cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2006; 13 (04) 274-279
- 26 Tannapfel A, Sommerer F, Benicke M. et al. Genetic and epigenetic alterations of the INK4a-ARF pathway in cholangiocarcinoma. J Pathol 2002; 197 (05) 624-631
- 27 Liggett Jr WH, Sidransky D. Role of the p16 tumor suppressor gene in cancer. J Clin Oncol 1998; 16 (03) 1197-1206
- 28 Ishikawa A, Sasaki M, Sato Y. et al. Frequent p16ink4a inactivation is an early and frequent event of intraductal papillary neoplasm of the liver arising in hepatolithiasis. Hum Pathol 2004; 35 (12) 1505-1514
- 29 Shio S, Kodama Y, Ida H. et al. Loss of RUNX3 expression by histone deacetylation is associated with biliary tract carcinogenesis. Cancer Sci 2011; 102 (04) 776-783
- 30 Andersen JB, Spee B, Blechacz BR. et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 2012; 142 (04) 1021-1031.e15
- 31 Merino-Azpitarte M, Lozano E, Perugorria MJ. et al. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J Hepatol 2017; 67 (01) 72-83
- 32 Huang Q, Liu Z, Xie F. et al. Fragile histidine triad (FHIT) suppresses proliferation and promotes apoptosis in cholangiocarcinoma cells by blocking PI3K-Akt pathway. Sci World J 2014; 2014: 179698
- 33 Foja S, Goldberg M, Schagdarsurengin U, Dammann R, Tannapfel A, Ballhausen WG. Promoter methylation and loss of coding exons of the fragile histidine triad (FHIT) gene in intrahepatic cholangiocarcinomas. Liver Int 2005; 25 (06) 1202-1208
- 34 Wang P, Dong Q, Zhang C. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 2013; 32 (25) 3091-3100
- 35 Tahiliani M, Koh KP, Shen Y. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324 (5929): 930-935
- 36 Xu W, Yang H, Liu Y. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19 (01) 17-30
- 37 Farshidfar F, Zheng S, Gingras M-CC. et al; Cancer Genome Atlas Network. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep 2017; 18 (11) 2780-2794
- 38 Saha SK, Parachoniak CA, Ghanta KS. et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 2014; 513 (7516): 110-114
- 39 Liu XF, Jiang H, Zhang CS, Yu SP, Wang ZQ, Su HL. Targeted drug regulation on methylation of p53-BAX mitochondrial apoptosis pathway affects the growth of cholangiocarcinoma cells. J Int Med Res 2012; 40 (01) 67-75
- 40 Nakamura K, Nakabayashi K, Htet Aung K. et al. DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status. PLoS One 2015; 10 (03) e0120545
- 41 Xiang J, Luo F, Chen Y, Zhu F, Wang J. si-DNMT1 restore tumor suppressor genes expression through the reversal of DNA hypermethylation in cholangiocarcinoma. Clin Res Hepatol Gastroenterol 2014; 38 (02) 181-189
- 42 Wang B, Li H, Yang R, Zhou S, Zou S. Decitabine inhibits the cell growth of cholangiocarcinoma in cultured cell lines and mouse xenografts. Oncol Lett 2014; 8 (05) 1919-1924
- 43 Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA. Epigenetics in hepatocellular carcinoma development and therapy: the tip of the iceberg. JHEP Rep 2020; 2 (06) 100167
- 44 Hu C, Liu X, Zeng Y, Liu J, Wu F. DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin Epigenetics 2021; 13 (01) 166
- 45 Colyn L, Bárcena-Varela M, Álvarez-Sola G. et al. Dual targeting of G9a and DNA methyltransferase-1 for the treatment of experimental cholangiocarcinoma. Hepatology 2021; 73 (06) 2380-2396
- 46 Waitkus MS, Diplas BH, Yan H. Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell 2018; 34 (02) 186-195
- 47 Abou-Alfa GK, Macarulla T, Javle MM. et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020; 21 (06) 796-807
- 48 Abou-Alfa GK, Macarulla Mercade T, Javle M. et al. ClarIDHy: a global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Ann Oncol 2019; 30: v872-v873
- 49 Lowery MA, Burris III HA, Janku F. et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol 2019; 4 (09) 711-720
- 50 Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol 2016; 27 (04) 599-608
- 51 Harding JJ, Lowery MA, Shih AH. et al. Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition. Cancer Discov 2018; 8 (12) 1540-1547
- 52 Saha SK, Gordan JD, Kleinstiver BP. et al. Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma. Cancer Discov 2016; 6 (07) 727-739
- 53 Molenaar RJ, Radivoyevitch T, Nagata Y. et al. Idh1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by idh1/2-mutant inhibitors. Clin Cancer Res 2018; 24 (07) 1705-1715
- 54 Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011; 21 (03) 381-395
- 55 Kim HG, Sung JY, Na K, Kim SW. Low H3K9me3 expression is associated with poor prognosis in patients with distal common bile duct cancer. In Vivo 2020; 34 (06) 3619-3626
- 56 Nakagawa S, Okabe H, Sakamoto Y. et al. Enhancer of zeste homolog 2 (EZH2) promotes progression of cholangiocarcinoma cells by regulating cell cycle and apoptosis. Ann Surg Oncol 2013; 20 (03, Suppl 3): S667-S675
- 57 Tang B, Du J, Li Y, Tang F, Wang Z, He S. EZH2 elevates the proliferation of human cholangiocarcinoma cells through the downregulation of RUNX3. Med Oncol 2014; 31 (11) 271
- 58 Nakagawa S, Sakamoto Y, Okabe H. et al. Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells. Oncol Rep 2014; 31 (02) 983-988
- 59 Revia S, Seretny A, Wendler L. et al. Histone H3K27 demethylase KDM6A is an epigenetic gatekeeper of mTORC1 signalling in cancer. Gut 2021; 4: 2021-325405
- 60 Pant K, Peixoto E, Richard S, Gradilone SA. Role of histone deacetylases in carcinogenesis: potential role in cholangiocarcinoma. Cells 2020; 9 (03) 1-14
- 61 Yin Y, Zhang M, Dorfman RG. et al. Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition. Cell Death Dis 2017; 8 (06) e2856
- 62 Gradilone SA, Radtke BN, Bogert PS, Huang BQ, Gajdos GB, LaRusso NF. HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Res 2013; 73 (07) 2259-2270
- 63 He JC, Yao W, Wang JM. et al. TACC3 overexpression in cholangiocarcinoma correlates with poor prognosis and is a potential anti-cancer molecular drug target for HDAC inhibitors. Oncotarget 2016; 7 (46) 75441-75456
- 64 Wang H, Li C, Jian Z, Ou Y, Ou J. TGF-β1 Reduces miR-29a expression to promote tumorigenicity and metastasis of cholangiocarcinoma by Targeting HDAC4. PLoS One 2015; 10 (10) e0136703
- 65 Baradari V, Höpfner M, Huether A, Schuppan D, Scherübl H. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J Gastroenterol 2007; 13 (33) 4458-4466
- 66 Sriraksa R, Limpaiboon T. Histone deacetylases and their inhibitors as potential therapeutic drugs for cholangiocarcinoma - cell line findings. Asian Pac J Cancer Prev 2013; 14 (04) 2503-2508
- 67 Wang B, Yang R, Wu Y. et al. Sodium valproate inhibits the growth of human cholangiocarcinoma in vitro and in vivo. Gastroenterol Res Pract 2013; 2013: 374593
- 68 Mayr C, Kiesslich T, Erber S. et al. HDAC screening identifies the HDAC class i inhibitor romidepsin as a promising epigenetic drug for biliary tract cancer. Cancers (Basel) 2021; 13 (15) 3862
- 69 Yang F, Zhao N, Ge D, Chen Y. Next-generation of selective histone deacetylase inhibitors. RSC Advances 2019; 9 (34) 19571-19583
- 70 Nakamura H, Arai Y, Totoki Y. et al. Genomic spectra of biliary tract cancer. Nat Genet 2015; 47 (09) 1003-1010
- 71 Kim KH, Kim W, Howard TP. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med 2015; 21 (12) 1491-1496
- 72 Jiao Y, Pawlik TM, Anders RA. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 2013; 45 (12) 1470-1473
- 73 Zou S, Li J, Zhou H. et al. Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 2014; 5 (May): 5696
- 74 Zhao S, Xu Y, Wu W. et al. ARID1A variations in cholangiocarcinoma: clinical significances and molecular mechanisms. Front Oncol 2021; 11 (June): 693295
- 75 Simbolo M, Vicentini C, Ruzzenente A. et al. Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma. Sci Rep 2018; 8 (01) 7119
- 76 Høgdall D, O'Rourke CJ, Taranta A, Oliveira DV, Andersen JB. Molecular pathogenesis and current therapy in intrahepatic cholangiocarcinoma. Dig Dis 2016; 34 (04) 440-451
- 77 Ribeiro-Silva C, Vermeulen W, Lans H. SWI/SNF: complex complexes in genome stability and cancer. DNA Repair (Amst) 2019; 77 (March): 87-95
- 78 LaFave LM, Béguelin W, Koche R. et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med 2015; 21 (11) 1344-1349
- 79 Feng H, Tong H, Yan J, He M, Chen W, Wang J. Genomic features and clinical characteristics of adolescents and young adults with cholangiocarcinoma. Front Oncol 2020; 9 (January): 1439
- 80 Rizzo A, Ricci AD, Tavolari S, Brandi G. Circulating tumor DNA in biliary tract cancer: current evidence and future perspectives. Cancer Genomics Proteomics 2020; 17 (05) 441-452
- 81 Cristiano S, Leal A, Phallen J. et al. Genome-wide cell-free DNA fragmentation in patients with cancer. Nature 2019; 570 (7761): 385-389
- 82 Sandhu DS, Shire AM, Roberts LR. Epigenetic DNA hypermethylation in cholangiocarcinoma: potential roles in pathogenesis, diagnosis and identification of treatment targets. Liver Int 2008; 28 (01) 12-27
- 83 Koga Y, Kitajima Y, Miyoshi A. et al. Tumor progression through epigenetic gene silencing of O(6)-methylguanine-DNA methyltransferase in human biliary tract cancers. Ann Surg Oncol 2005; 12 (05) 354-363
- 84 Nishizaki M, Sasaki J, Fang B. et al. Synergistic tumor suppression by coexpression of FHIT and p53 coincides with FHIT-mediated MDM2 inactivation and p53 stabilization in human non-small cell lung cancer cells. Cancer Res 2004; 64 (16) 5745-5752
- 85 Tischoff I, Markwarth A, Witzigmann H. et al. Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors. Int J Cancer 2005; 115 (05) 684-689
- 86 Liao W, Liu J, Liu B. et al. JIB–04 induces cell apoptosis via activation of the p53/Bcl–2/caspase pathway in MHCC97H and HepG2 cells. Oncol Rep 2018; 40 (06) 3812-3820