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DNMT1 as a therapeutic target in pancreatic cancer: mechanisms and clinical implications

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Abstract

Background

Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating cancer types with a 5-year survival rate of only 9%. PDAC is one of the leading causes of cancer-related deaths in both genders. Epigenetic alterations may lead to the suppression of tumor suppressor genes, and DNA methylation is a predominant epigenetic modification. DNA methyltransferase 1 (DNMT1) is required for maintaining patterns of DNA methylation during cellular replication. Accumulating evidence has implicated the oncogenic roles of DNMT1 in various malignancies including PDACs.

Conclusions

Herein, the expression profiles, oncogenic roles, regulators and inhibitors of DNMT1 in PDACs are presented and discussed. DNMT1 is overexpressed in PDAC cases compared with non-cancerous pancreatic ducts, and its expression gradually increases from pre-neoplastic lesions to PDACs. DNMT1 plays oncogenic roles in suppressing PDAC cell differentiation and in promoting their proliferation, migration and invasion, as well as in induction of the self-renewal capacity of PDAC cancer stem cells. These effects are achieved via promoter hypermethylation of tumor suppressor genes, including cyclin-dependent kinase inhibitors (e.g., p14, p15, p16, p21 and p27), suppressors of epithelial-mesenchymal transition (e.g., E-cadherin) and tumor suppressor miRNAs (e.g., miR-148a, miR-152 and miR-17-92 cluster). Pre-clinical investigations have shown the potency of novel non-nucleoside DNMT1 inhibitors against PDAC cells. Finally, phase I/II clinical trials of DNMT1 inhibitors (azacitidine, decitabine and guadecitabine) in PDAC patients are currently underway, where these inhibitors have the potential to sensitize PDACs to chemotherapy and immune checkpoint blockade therapy.

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References

  1. R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019)

    PubMed  Google Scholar 

  2. Zhang J, Zhang L, Li C, Yang C, Li L, Song S, Wu H, Liu F, Wang L, Gu J, LOX-1 is a poor prognostic indicator and induces epithelial-mesenchymal transition and metastasis in pancreatic cancer patients. Cell. Oncol. 41,73–84 (2018)

  3. M. Momeny, F. Esmaeili, S. Hamzehlou, H. Yousefi, S. Javadikooshesh, V. Vahdatirad, Z. Alishahi, S.H. Mousavipak, D. Bashash, A.R. Dehpour, S.M. Tavangar, J. Tavakkoly-Bazzaz, P. Haddad, F. Kordbacheh, K. Alimoghaddam, A. Ghavamzadeh, S.H. Ghaffari, The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cell. Oncol. 42, 491–504 (2019)

  4. W. Chen, R. Zheng, P.D. Baade, S. Zhang, H. Zeng, F. Bray, A. Jemal, X.Q. Yu, J. He, Cancer statistics in China, 2015. CA Cancer J. Clin. 66, 115–132 (2016)

    Google Scholar 

  5. A.V. Biankin, J.G. Kench, S.A. Biankin, C.S. Lee, A.L. Morey, F.P. Dijkman, M.J. Coleman, R.L. Sutherland, S.M. Henshall, Pancreatic intraepithelial neoplasia in association with intraductal papillary mucinous neoplasms of the pancreas: implications for disease progression and recurrence. Am. J. Surg. Pathol. 28, 1184–1192 (2004)

    PubMed  Google Scholar 

  6. E. Vidal, S. Sayols, S. Moran, A. Guillaumet-Adkins, M.P. Schroeder, R. Royo, M. Orozco, M. Gut, I. Gut, N. Lopez-Bigas, H. Heyn, M. Esteller, A DNA methylation map of human cancer at single base-pair resolution. Oncogene 36, 5648–5657 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. M. Kim, J. Costello, DNA methylation: an epigenetic mark of cellular memory. Exp. Mol. Med. 49, e322 (2017)

  8. T. Hamidi, A.K. Singh, T. Chen, Genetic alterations of DNA methylation machinery in human diseases. Epigenomics 7, 247–265 (2015)

    CAS  PubMed  Google Scholar 

  9. J.J. Zhang, Y. Zhu, Y. Zhu, J.L. Wu, W.B. Liang, R. Zhu, Z.K. Xu, Q. Du, Y. Miao, Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma. Clin. Transl. Oncol. 14, 116–124 (2012)

    CAS  PubMed  Google Scholar 

  10. J. Gao, L. Wang, J. Xu, J. Zheng, X. Man, H. Wu, J. Jin, K. Wang, H. Xiao, S. Li, Z. Li, Aberrant DNA methyltransferase expression in pancreatic ductal adenocarcinoma development and progression. J. Exp. Clin. Cancer Res. 32, 86 (2013)

  11. W. Wang, J. Gao, X.H. Man, Z.S. Li, Y.F. Gong, Significance of DNA methyltransferase-1 and histone deacetylase-1 in pancreatic cancer. Oncol. Rep. 21, 1439–1447 (2009)

    CAS  PubMed  Google Scholar 

  12. D.F. Peng, Y. Kanai, M. Sawada, S. Ushijima, N. Hiraoka, T. Kosuge, S. Hirohashi, Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas. Cancer Sci. 96, 403–408 (2005)

    CAS  PubMed  Google Scholar 

  13. Z. Tang, B. Kang, C. Li, T. Chen, Z. Zhang, GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 47, W556–W560 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. N. Cancer Genome Atlas Research, J.N. Weinstein, E.A. Collisson, G.B. Mills, K.R. Shaw, B.A. Ozenberger, K. Ellrott, I. Shmulevich, C. Sander, J.M. Stuart, The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013)

  15. G.T. Consortium, Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015)

    Google Scholar 

  16. R.A. Moffitt, R. Marayati, E.L. Flate, K.E. Volmar, S.G. Loeza, K.A. Hoadley, N.U. Rashid, L.A. Williams, S.C. Eaton, A.H. Chung, J.K. Smyla, J.M. Anderson, H.J. Kim, D.J. Bentrem, M.S. Talamonti, C.A. Iacobuzio-Donahue, M.A. Hollingsworth, J.J. Yeh, Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. G. Lomberk, Y. Blum, R. Nicolle, A. Nair, K.S. Gaonkar, L. Marisa, A. Mathison, Z. Sun, H. Yan, N. Elarouci, L. Armenoult, M. Ayadi, T. Ordog, J.H. Lee, G. Oliver, E. Klee, V. Moutardier, O. Gayet, B. Bian, P. Duconseil, M. Gilabert, M. Bigonnet, S. Garcia, O. Turrini, J.R. Delpero, M. Giovannini, P. Grandval, M. Gasmi, V. Secq, A. De Reynies, N. Dusetti, J. Iovanna, R. Urrutia, Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. Nat. Commun. 9, 1978 (2018)

    PubMed  PubMed Central  Google Scholar 

  18. R. Nicolle, Y. Blum, L. Marisa, C. Loncle, O. Gayet, V. Moutardier, O. Turrini, M. Giovannini, B. Bian, M. Bigonnet, M. Rubis, N. Elarouci, L. Armenoult, M. Ayadi, P. Duconseil, M. Gasmi, M. Ouaissi, A. Maignan, G. Lomberk, J.M. Boher, J. Ewald, E. Bories, J. Garnier, A. Goncalves, F. Poizat, J.L. Raoul, V. Secq, S. Garcia, P. Grandval, M. Barraud-Blanc, E. Norguet, M. Gilabert, J.R. Delpero, J. Roques, E. Calvo, F. Guillaumond, S. Vasseur, R. Urrutia, A. de Reynies, N. Dusetti, and J. Iovanna, Pancreatic adenocarcinoma therapeutic targets revealed by tumor-stroma cross-talk analyses in patient-derived xenografts. Cell. Rep. 21, 2458–2470 (2017)

  19. J. Gao, B.A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S.O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, E. Cerami, C. Sander, N. Schultz, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013)

  20. Cancer Genome Atlas Research Network, Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 32, 185–203 e113 (2017)

  21. D.F. Peng, Y. Kanai, M. Sawada, S. Ushijima, N. Hiraoka, S. Kitazawa, S. Hirohashi, DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27, 1160–1168 (2006)

    CAS  PubMed  Google Scholar 

  22. M. Xu, J. Gao, Y.Q. Du, D.J. Gao, Y.Q. Zhang, Z.S. Li, Y.L. Zhang, Y.F. Gong, P. Xu, Reduction of pancreatic cancer cell viability and induction of apoptosis mediated by siRNA targeting DNMT1 through suppression of total DNA methyltransferase activity. Mol. Med. Rep. 3, 699–704 (2010)

  23. V. Barra, T. Schillaci, L. Lentini, G. Costa, A. Di Leonardo, Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells. Cell Div. 7, 2 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. X. Wang, B. Li, DNMT1 regulates human endometrial carcinoma cell proliferation. Onco Targets Ther. 10, 1865–1873 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. S.L. Peters, R.A. Hlady, J. Opavska, D. Klinkebiel, S. Novakova, L.M. Smith, R.E. Lewis, A.R. Karpf, M.A. Simpson, L. Wu, R. Opavsky, Essential role for Dnmt1 in the prevention and maintenance of MYC-induced T-cell lymphomas. Mol. Cell. Biol. 33, 4321–4333 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. C. Florean, M. Schnekenburger, J.Y. Lee, K.R. Kim, A. Mazumder, S. Song, J.M. Kim, C. Grandjenette, J.G. Kim, A.Y. Yoon, M. Dicato, K.W. Kim, C. Christov, B.W. Han, P. Proksch, M. Diederich, Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells. Oncotarget 7, 24027–24049 (2016)

    PubMed  PubMed Central  Google Scholar 

  27. J.P. Neoptolemos, D.D. Stocken, H. Friess, C. Bassi, J.A. Dunn, H. Hickey, H. Beger, L. Fernandez-Cruz, C. Dervenis, F. Lacaine, M. Falconi, P. Pederzoli, A. Pap, D. Spooner, D.J. Kerr, M.W. Buchler and C. European Study Group for Pancreatic, A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 350, 1200–1210 (2004)

  28. C.C. Hsu, C.L. Wolfgang, D.A. Laheru, T.M. Pawlik, M.J. Swartz, J.M. Winter, R. Robinson, B.H. Edil, A.K. Narang, M.A. Choti, R.H. Hruban, J.L. Cameron, R.D. Schulick, J.M. Herman, Early mortality risk score: identification of poor outcomes following upfront surgery for resectable pancreatic cancer. J. Gastrointest. Surg. 16, 753–761 (2012)

  29. S. Wen, B. Zhan, J. Feng, W. Hu, X. Lin, J. Bai, H. Huang, Non-invasively predicting differentiation of pancreatic cancer through comparative serum metabonomic profiling. BMC Cancer 17, 708 (2017)

    PubMed  PubMed Central  Google Scholar 

  30. F. Zammarchi, M. Morelli, M. Menicagli, C. Di Cristofano, K. Zavaglia, A. Paolucci, D. Campani, P. Aretini, U. Boggi, F. Mosca, A. Cavazzana, L. Cartegni, G. Bevilacqua, C.M. Mazzanti, KLF4 is a novel candidate tumor suppressor gene in pancreatic ductal carcinoma. Am. J. Pathol. 178, 361–372 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. V.K. Xie, Z. Li, Y. Yan, Z. Jia, X. Zuo, Z. Ju, J. Wang, J. Du, D. Xie, K. Xie, D. Wei, DNA-methyltransferase 1 induces dedifferentiation of pancreatic cancer cells through silencing of Kruppel-like factor 4 expression. Clin. Cancer Res. 23, 5585–5597 (2017)

  32. L. Huang, R.L. Wu, A.M. Xu, Epithelial-mesenchymal transition in gastric cancer. Am. J. Transl. Res. 7, 2141–2158 (2015)

  33. H. Yu, Y. Shen, J. Hong, Q. Xia, F. Zhou, X. Liu, The contribution of TGF-beta in epithelial-mesenchymal transition (EMT): Down-regulation of E-cadherin via Snail. Neoplasma 62, 1–15 (2015)

  34. E.L. Deer, J. Gonzalez-Hernandez, J.D. Coursen, J.E. Shea, J. Ngatia, C.L. Scaife, M.A. Firpo, S.J. Mulvihill, Phenotype and genotype of pancreatic cancer cell lines. Pancreas 39, 425–435 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. H. Han, X. Yang, K. Pandiyan, G. Liang, Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One 8, e75136 (2013)

  36. J. Cheng, H. Yang, J. Fang, L. Ma, R. Gong, P. Wang, Z. Li, Y. Xu, Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation. Nat. Commun. 6, 7023 (2015)

  37. A. Fukagawa, H. Ishii, K. Miyazawa, M. Saitoh, deltaEF1 associates with DNMT1 and maintains DNA methylation of the E-cadherin promoter in breast cancer cells. Cancer Med. 4, 125–135 (2015)

    CAS  PubMed  Google Scholar 

  38. H. Yu, W. Yang, MiR-211 is epigenetically regulated by DNMT1 mediated methylation and inhibits EMT of melanoma cells by targeting RAB22A. Biochem. Biophys. Res. Commun. 476, 400–405 (2016)

  39. X. Wang, Z. Liang, X. Xu, J. Li, Y. Zhu, S. Meng, S. Li, S. Wang, B. Xie, A. Ji, B. Liu, X. Zheng, L. Xie, miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer. Cell Death Dis. 7, e2503 (2016)

  40. L. Huang, B. Hu, J. Ni, J. Wu, W. Jiang, C. Chen, L. Yang, Y. Zeng, R. Wan, G. Hu, X. Wang, Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis. J. Exp. Clin. Cancer Res. 35, 27 (2016)

  41. M.W. Khan, A. Saadalla, A.H. Ewida, K. Al-Katranji, G. Al-Saoudi, Z.T. Giaccone, F. Gounari, M. Zhang, D.A. Frank, K. Khazaie, The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol. Immunother. 67, 13–23 (2018)

    CAS  PubMed  Google Scholar 

  42. R.H. Shoemaker, J.T. Fox, M.M. Juliana, F.L. Moeinpour, C.J. Grubbs, Evaluation of the STAT3 inhibitor GLG302 for the prevention of estrogen receptorpositive and negative mammary cancers. Oncol. Rep. 42, 1205–1213 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. A Phase I Trial of WP1066 in Patients With Recurrent Malignant Glioma and Brain Metastasis From Melanoma. (2013) https://clinicaltrials.gov/ct2/show/NCT01904123 Accessed 23 Dec 2019

  44. Phase I Study of TTI-101, an Oral Inhibitor of Signal Transducer and Activator of Transcription (STAT) 3, in Patients With Advanced Cancers. (2017) https://clinicaltrials.gov/ct2/show/NCT03195699 Accessed 23 Dec 2019

  45. S. Dawood, L. Austin, M. Cristofanilli, Cancer stem cells: implications for cancer therapy. Oncology (Williston Park) 28, 1101–1107 (2014) 1110

  46. S. Santamaria, M. Delgado, L. Kremer, J.A. Garcia-Sanz, Will a mAb-based immunotherapy directed against cancer stem cells be feasible? Front. Immunol. 8, 1509 (2017)

  47. Z. Yang, N. Zhao, J. Cui, H. Wu, J. Xiong, T. Peng, Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210. Cell. Oncol. 43, 123–136 (2020)

  48. E. Dalla Pozza, I. Dando, G. Biondani, J. Brandi, C. Costanzo, E. Zoratti, M. Fassan, F. Boschi, D. Melisi, D. Cecconi, M.T. Scupoli, A. Scarpa, M. Palmieri, Pancreatic ductal adenocarcinoma cell lines display a plastic ability to bidirectionally convert into cancer stem cells. Int. J. Oncol. 46, 1099–1108 (2015)

  49. C. Di Carlo, J. Brandi, D. Cecconi, Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma. World J. Stem Cells 10, 172–182 (2018)

  50. S. Zagorac, S. Alcala, G. Fernandez Bayon, T. Bou Kheir, M. Schoenhals, A. Gonzalez-Neira, M. Fernandez Fraga, A. Aicher, C. Heeschen, B. Sainz Jr., DNMT1 inhibition reprograms pancreatic cancer stem cells via upregulation of the miR-17-92 cluster. Cancer Res. 76, 4546–4558 (2016)

  51. M.M. Valenzuela, J.W. Neidigh, N.R. Wall, Antimetabolite treatment for pancreatic cancer. Chemotherapy (Los Angel) 3, pii: 137 (2014)

  52. H. Denis, M.N. Ndlovu, F. Fuks, Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBO Rep. 12, 647–656 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  53. W. Qin, H. Leonhardt, G. Pichler, Regulation of DNA methyltransferase 1 by interactions and modifications. Nucleus 2, 392–402 (2011)

    PubMed  Google Scholar 

  54. W. Qin, H. Leonhardt, F. Spada, Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1. J. Cell. Biochem. 112, 439–444 (2011)

    CAS  PubMed  Google Scholar 

  55. M. Felle, S. Joppien, A. Nemeth, S. Diermeier, V. Thalhammer, T. Dobner, E. Kremmer, R. Kappler, G. Langst, The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1. Nucleic Acids Res. 39, 8355–8365 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. S. Shaker, M. Bernstein, L.F. Momparler, R.L. Momparler, Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2’-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemic cells. Leuk. Res. 27, 437–444 (2003)

  57. A. Hurtubise, M.L. Bernstein, R.L. Momparler, Preclinical evaluation of the antineoplastic action of 5-aza-2’-deoxycytidine and different histone deacetylase inhibitors on human Ewing’s sarcoma cells. Cancer Cell Int. 8, 16 (2008)

    PubMed  PubMed Central  Google Scholar 

  58. Y. Yang, X. Hua, In search of tumor suppressing functions of menin. Mol. Cell. Endocrinol. 265–266, 34–41 (2007)

    PubMed  PubMed Central  Google Scholar 

  59. W. Lin, H. Watanabe, S. Peng, J.M. Francis, N. Kaplan, C.S. Pedamallu, A. Ramachandran, A. Agoston, A.J. Bass, M. Meyerson, Dynamic epigenetic regulation by menin during pancreatic islet tumor formation. Mol. Cancer Res. 13, 689–698 (2015)

  60. P. Cheng, Y.F. Wang, G. Li, S.S. Yang, C. Liu, H. Hu, G. Jin, X.G. Hu, Interplay between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of the Hedgehog signaling pathway. Cancer Lett. 370, 136–144 (2016)

    CAS  PubMed  Google Scholar 

  61. M.H. Huang, Y.W. Chou, M.H. Li, T.E. Shih, S.Z. Lin, H.M. Chuang, T.W. Chiou, H.L. Su, H.J. Harn, Epigenetic targeting DNMT1 of pancreatic ductal adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through hedgehog pathway inhibition. Pharmacol. Res. 139, 50–61 (2019)

  62. P.A. Puolakkainen, R.A. Brekken, S. Muneer, E.H. Sage, Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol. Cancer Res. 2, 215–224 (2004)

  63. M. Erkan, J. Kleeff, I. Esposito, T. Giese, K. Ketterer, M.W. Buchler, N.A. Giese, H. Friess, Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene 24, 4421–4432 (2005)

    CAS  PubMed  Google Scholar 

  64. Y. Li, X. Zhang, J. Yang, Y. Zhang, D. Zhu, L. Zhang, Y. Zhu, D. Li, J. Zhou, Methylation of BNIP3 in pancreatic cancer inhibits the induction of mitochondrial-mediated tumor cell apoptosis. Oncotarget 8, 63208–63222 (2017)

    PubMed  PubMed Central  Google Scholar 

  65. M. Azizi, P. Fard-Esfahani, H. Mahmoodzadeh, M.S. Fazeli, K. Azadmanesh, S. Zeinali, L. Teimoori-Toolabi, MiR-377 reverses cancerous phenotypes of pancreatic cells via suppressing DNMT1 and demethylating tumor suppressor genes. Epigenomics 9, 1059–1075 (2017)

    CAS  PubMed  Google Scholar 

  66. M. Azizi, L. Teimoori-Toolabi, M.K. Arzanani, K. Azadmanesh, P. Fard-Esfahani, S. Zeinali, MicroRNA-148b and microRNA-152 reactivate tumor suppressor genes through suppression of DNA methyltransferase-1 gene in pancreatic cancer cell lines. Cancer Biol. Ther. 15, 419–427 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Y. Xiang, N. Ma, D. Wang, Y. Zhang, J. Zhou, G. Wu, R. Zhao, H. Huang, X. Wang, Y. Qiao, F. Li, D. Han, L. Wang, G. Zhang, X. Gao, MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine. Oncogene 33, 378–386 (2014)

    CAS  PubMed  Google Scholar 

  68. C. Sui, F. Meng, Y. Li, Y. Jiang, miR-148b reverses cisplatin-resistance in non-small cell cancer cells via negatively regulating DNA (cytosine-5)-methyltransferase 1(DNMT1) expression. J. Transl. Med. 13, 132 (2015)

  69. D. Sengupta, M. Deb, S.K. Rath, S. Kar, S. Parbin, N. Pradhan, S.K. Patra, DNA methylation and not H3K4 trimethylation dictates the expression status of miR-152 gene which inhibits migration of breast cancer cells via DNMT1/CDH1 loop. Exp. Cell Res. 346, 176–187 (2016)

    CAS  PubMed  Google Scholar 

  70. Q. Zhan, Y. Fang, X. Deng, H. Chen, J. Jin, X. Lu, C. Peng, H. Li, B. Shen, The interplay between miR-148a and DNMT1 might be exploited for pancreatic cancer therapy. Cancer Invest. 33, 267–275 (2015)

  71. L. Hong, G. Sun, L. Peng, Y. Tu, Z. Wan, H. Xiong, Y. Li, W. Xiao, The interaction between miR148a and DNMT1 suppresses cell migration and invasion by reactivating tumor suppressor genes in pancreatic cancer. Oncol. Rep. 40, 2916–2925 (2018)

    CAS  PubMed  Google Scholar 

  72. T.K. Kelly, D.D. De Carvalho, P.A. Jones, Epigenetic modifications as therapeutic targets. Nat. Biotechnol. 28, 1069–1078 (2010)

  73. K. Lund, J.J. Cole, N.D. VanderKraats, T. McBryan, N.A. Pchelintsev, W. Clark, M. Copland, J.R. Edwards, P.D. Adams, DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML. Genome Biol. 15, 406 (2014)

    PubMed  PubMed Central  Google Scholar 

  74. B.J. Wouters, R. Delwel, Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 127, 42–52 (2016)

    CAS  PubMed  Google Scholar 

  75. L. Gailhouste, L.C. Liew, I. Hatada, H. Nakagama, T. Ochiya, Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells. Cell Death Dis. 9, 468 (2018)

    PubMed  PubMed Central  Google Scholar 

  76. M.N. Dastjerdi, Z. Babazadeh, M. Salehi, B. Hashemibeni, M. Kazemi, Comparison of the anti-cancer effect of Disulfiram and 5-Aza-CdR on pancreatic cancer cell line PANC-1. Adv. Biomed. Res. 3, 156 (2014)

  77. O. Gayet, C. Loncle, P. Duconseil, M. Gilabert, M.B. Lopez, V. Moutardier, O. Turrini, E. Calvo, J. Ewald, M. Giovannini, M. Gasmi, E. Bories, M. Barthet, M. Ouaissi, A. Goncalves, F. Poizat, J.L. Raoul, V. Secq, S. Garcia, P. Viens, N. Dusetti, J. Iovanna, A subgroup of pancreatic adenocarcinoma is sensitive to the 5-aza-dC DNA methyltransferase inhibitor. Oncotarget 6, 746–754 (2015)

    PubMed  Google Scholar 

  78. F.P. Pan, H.K. Zhou, H.Q. Bu, Z.Q. Chen, H. Zhang, L.P. Xu, J. Tang, Q.J. Yu, Y.Q. Chu, J. Pan, Y. Fei, S.Z. Lin, D.L. Liu, L. Chen, Emodin enhances the demethylation by 5-Aza-CdR of pancreatic cancer cell tumor-suppressor genes P16, RASSF1A and ppENK. Oncol. Rep. 35, 1941–1949 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. M. Thakar, Y. Hu, M. Morreale, L. Lerner, W. Ying Lin, R. Sen, Y. Cai, E. Karunasena, M. Thakar, S. Saggi, H. Keer, N. Ahuja, A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent. PLoS One 13, e0199130 (2018)

  80. A Phase 1b Study: Treatment of Refractory Pancreatic Adenocarcinoma and Advanced Soft Tissue or Bone Sarcomas Using Decitabine Combined With Gemcitabine. (2016) https://clinicaltrials.gov/ct2/show/NCT02959164 Accessed 18 Dec 2019

  81. A Phase II Trial to Improve Outcomes in Patients With Resected Pancreatic Adenocarcinoma at High Risk for Recurrence Using Epigenetic Therapy. (2013) https://clinicaltrials.gov/ct2/show/NCT01845805 Accessed 18 Dec 2019

  82. Clinical Study of Low Dose of Decitabine Combined With Gemcitabine in First-line Treatment of Locally Advanced, Unresectable or Metastatic Pancreatic Cancer. (2016) https://clinicaltrials.gov/ct2/show/NCT02685228 Accessed 18 Dec 2019

  83. O. Goodyear, A. Agathanggelou, I. Novitzky-Basso, S. Siddique, T. McSkeane, G. Ryan, P. Vyas, J. Cavenagh, T. Stankovic, P. Moss, C. Craddock, Induction of a CD8 + T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 116, 1908–1918 (2010)

    CAS  PubMed  Google Scholar 

  84. A.O. Gang, T.M. Frosig, M.K. Brimnes, R. Lyngaa, M.B. Treppendahl, K. Gronbaek, I.H. Dufva, P.T. Straten, S.R. Hadrup, 5-Azacytidine treatment sensitizes tumor cells to T-cell mediated cytotoxicity and modulates NK cells in patients with myeloid malignancies. Blood Cancer J. 4, e197 (2014)

  85. S.R. James, P.A. Link, A.R. Karpf, Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b. Oncogene 25, 6975–6985 (2006)

    CAS  PubMed  Google Scholar 

  86. A. Loriot, E. De Plaen, T. Boon, C. De Smet, Transient down-regulation of DNMT1 methyltransferase leads to activation and stable hypomethylation of MAGE-A1 in melanoma cells. J. Biol. Chem. 281, 10118–10126 (2006)

    CAS  PubMed  Google Scholar 

  87. P.F. Cartron, C. Blanquart, E. Hervouet, M. Gregoire, F.M. Vallette, HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression. Mol. Oncol. 7, 452–463 (2013)

  88. Phase II Open-Label, Single-Center Study Evaluating Safety and Efficacy of Pembrolizumab Following Induction With the Hypomethylating Agent Azacitidine in Patients With Advanced Pancreatic Cancer After Failure of First-Line Therapy. (2017) https://clinicaltrials.gov/ct2/show/NCT03264404 Accessed 18 Dec 2019

  89. L. Abushahin, V. Monga, D. Berg, C. Chandrasekharan, M. Tanas, M. Henry, M. Mckay, S. Mott, M. Milhem, in AACR Annual Meeting 2018, (Chicago, IL, 2018), p. Abstract nr CT136

  90. A Phase Ib Study of Guadecitabine (SGI-110) and Durvalumab (MEDI 4736) in Patients With Advanced Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, and Cholangiocarcinoma/Gallbladder Cancer. (2018) https://clinicaltrials.gov/ct2/show/NCT03257761 Accessed 18 Nov 2019

  91. K.K. Wong, C.H. Lawrie, T.M. Green, Oncogenic roles and inhibitors of DNMT1, DNMT3A, and DNMT3B in acute myeloid leukaemia. Biomark. Insights 14, 1177271919846454 (2019)

  92. T. Conroy, F. Desseigne, M. Ychou, O. Bouche, R. Guimbaud, Y. Becouarn, A. Adenis, J.L. Raoul, S. Gourgou-Bourgade, C. de la Fouchardiere, J. Bennouna, J.B. Bachet, F. Khemissa-Akouz, D. Pere-Verge, C. Delbaldo, E. Assenat, B. Chauffert, P. Michel, C. Montoto-Grillot, M. Ducreux, U. Groupe Tumeurs Digestives of and P. Intergroup, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011)

  93. S. Coral, G. Parisi, H.J. Nicolay, F. Colizzi, R. Danielli, E. Fratta, A. Covre, P. Taverna, L. Sigalotti, M. Maio, Immunomodulatory activity of SGI-110, a 5-aza-2’-deoxycytidine-containing demethylating dinucleotide. Cancer Immunol. Immunother. 62, 605–614 (2013)

    CAS  PubMed  Google Scholar 

  94. P. Srivastava, B.E. Paluch, J. Matsuzaki, S.R. James, G. Collamat-Lai, P. Taverna, A.R. Karpf, E.A. Griffiths, Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics 10, 237–246 (2015)

    PubMed  PubMed Central  Google Scholar 

  95. P. Srivastava, B.E. Paluch, J. Matsuzaki, S.R. James, G. Collamat-Lai, J. Karbach, M.J. Nemeth, P. Taverna, A.R. Karpf, E.A. Griffiths, Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk. Res. 38, 1332–1341 (2014)

  96. Y. Li, J. Deuring, M.P. Peppelenbosch, E.J. Kuipers, C. de Haar, C.J. van der Woude, IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer. Carcinogenesis 33, 1889–1896 (2012)

    CAS  PubMed  Google Scholar 

  97. R. Pathania, S. Ramachandran, S. Elangovan, R. Padia, P. Yang, S. Cinghu, R. Veeranan-Karmegam, P. Arjunan, J.P. Gnana-Prakasam, F. Sadanand, L. Pei, C.S. Chang, J.H. Choi, H. Shi, S. Manicassamy, P.D. Prasad, S. Sharma, V. Ganapathy, R. Jothi, M. Thangaraju, DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat. Commun. 6, 6910 (2015)

  98. Y. Hu, Z. Ma, Y. He, W. Liu, Y. Su, Z. Tang, LncRNA-SNHG1 contributes to gastric cancer cell proliferation by regulating DNMT1. Biochem. Biophys. Res. Commun. 491, 926–931 (2017)

  99. S.K. Loo, E.S. Ch’ng, C.H. Lawrie, M.A. Muruzabal, A. Gaafar, M.P. Pomposo, A. Husin, M.S. Md Salleh, A.H. Banham, L.M. Pedersen, M.B. Moller, T.M. Green, K.K. Wong, DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas. Pathology 49, 731–739 (2017)

    CAS  PubMed  Google Scholar 

  100. J.H. Yoon, Y.J. Choi, W.S. Choi, H. Ashktorab, D.T. Smoot, S.W. Nam, J.Y. Lee, W.S. Park, GKN1-miR-185-DNMT1 axis suppresses gastric carcinogenesis through regulation of epigenetic alteration and cell cycle. Clin. Cancer Res. 19, 4599–4610 (2013)

  101. C.C. Liu, J.H. Lin, T.W. Hsu, K. Su, A.F. Li, H.S. Hsu, S.C. Hung, IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation. Int. J. Cancer 136, 547–559 (2015)

  102. S.K. Loo, S.S. Ab Hamid, M. Musa, K.K. Wong, DNMT1 is associated with cell cycle and DNA replication gene sets in diffuse large B-cell lymphoma. Pathol. Res. Pract. 214, 134–143 (2018)

    CAS  PubMed  Google Scholar 

  103. S. Vijayaraghavan, S. Moulder, K. Keyomarsi, R.M. Layman, Inhibiting CDK in Cancer Therapy: Current Evidence and Future Directions. Target. Oncol. 13, 21–38 (2018)

  104. S.M. Nur Husna, H.T. Tan, R. Mohamud, A. Dyhl-Polk, K.K. Wong, Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther. Adv. Med. Oncol. 10, 1758835918808509 (2018)

  105. C.F. Lee, D.S. Ou, S.B. Lee, L.H. Chang, R.K. Lin, Y.S. Li, A.K. Upadhyay, X. Cheng, Y.C. Wang, H.S. Hsu, M. Hsiao, C.W. Wu, L.J. Juan, hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing. J. Clin. Invest. 120, 2920–2930 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Y. Zhang, V.K. Subbaiah, D. Rajagopalan, C.Y. Tham, L.N. Abdullah, T.B. Toh, M. Gong, T.Z. Tan, S.P. Jadhav, A.K. Pandey, N. Karnani, E.K. Chow, J.P. Thiery, S. Jha, TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program. J. Mol. Cell. Biol. 8, 384–399 (2016)

  107. Z. Chen, S. Liu, L. Tian, M. Wu, F. Ai, W. Tang, L. Zhao, J. Ding, L. Zhang, A. Tang, miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1. Oncotarget 6, 38139–38150 (2015)

    PubMed  PubMed Central  Google Scholar 

  108. D.S. Choi, E. Blanco, Y.S. Kim, A.A. Rodriguez, H. Zhao, T.H. Huang, C.L. Chen, G. Jin, M.D. Landis, L.A. Burey, W. Qian, S.M. Granados, B. Dave, H.H. Wong, M. Ferrari, S.T. Wong, J.C. Chang, Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 32, 2309–2323 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Y. Teng, X. Yu, H. Yuan, L. Guo, W. Jiang, S.H. Lu, DNMT1 ablation suppresses tumorigenesis by inhibiting the self-renewal of esophageal cancer stem cells. Oncotarget 9, 18896–18907 (2018)

    PubMed  PubMed Central  Google Scholar 

  110. W.H. Yan, A.F. Lin, C.C. Chang, S. Ferrone, Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2’-deoxycytidine. Cell Res. 15, 523–531 (2005)

    PubMed  Google Scholar 

  111. J. Zhou, Y. Li, Y. Yao, L. Wang, L. Gao, X. Gao, X. Luo, J. Li, M. Jiang, M. Zhou, L. Wang, L. Yu, The cancertestis antigen NXF2 is activated by the hypomethylating agent decitabine in acute leukemia cells in vitro and in vivo. Mol. Med. Rep. 8, 1549–1555 (2013)

  112. X. Li, Q. Mei, J. Nie, X. Fu, W. Han, Decitabine: a promising epi-immunotherapeutic agent in solid tumors. Expert Rev. Clin. Immunol. 11, 363–375 (2015)

  113. H. Fan, X. Lu, X. Wang, Y. Liu, B. Guo, Y. Zhang, W. Zhang, J. Nie, K. Feng, M. Chen, Y. Zhang, Y. Wang, F. Shi, X. Fu, H. Zhu, W. Han, Low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors: a phase I/II report. J. Immunol. Res. 2014, 371087 (2014)

  114. M. Chen, J. Nie, Y. Liu, X. Li, Y. Zhang, M.V. Brock, K. Feng, Z. Wu, X. Li, L. Shi, S. Li, M. Guo, Q. Mei, W. Han, Phase Ib/II study of safety and efficacy of low-dose decitabine-primed chemoimmunotherapy in patients with drug-resistant relapsed/refractory alimentary tract cancer. Int. J. Cancer 143, 1530–1540 (2018)

  115. S. Krishna, S. Shukla, A.D. Lakra, S.M. Meeran, M.I. Siddiqi, Identification of potent inhibitors of DNA methyltransferase 1 (DNMT1) through a pharmacophore-based virtual screening approach. J. Mol. Graph. Model. 75, 174–188 (2017)

    CAS  PubMed  Google Scholar 

  116. V. Miletic, I. Odorcic, P. Nikolic, Z.M. Svedruzic, In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1. PLoS One 12, e0174410 (2017)

  117. S.C. Wang, T.H. Lee, C.H. Hsu, Y.J. Chang, M.S. Chang, Y.C. Wang, Y.S. Ho, W.C. Wen, R.K. Lin, Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. J. Agric. Food Chem. 62, 5625–5635 (2014)

    CAS  PubMed  Google Scholar 

  118. J.R. Weng, I.L. Lai, H.C. Yang, C.N. Lin, L.Y. Bai, Identification of kazinol Q, a natural product from Formosan plants, as an inhibitor of DNA methyltransferase. Phytother. Res. 28, 49–54 (2014)

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Acknowledgements

This work was supported by the Bridging Grant (304.PPSP.6316332), Universiti Sains Malaysia, awarded to K.K.W.

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  1. Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

    Kah Keng Wong

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Wong, K. DNMT1 as a therapeutic target in pancreatic cancer: mechanisms and clinical implications. Cell Oncol. 43, 779–792 (2020). https://doi.org/10.1007/s13402-020-00526-4

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