Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.
Cell Oncol (Dordr). 2020 Oct;43(5):779-792. doi: 10.1007/s13402-020-00526-4. Epub 2020 Jun 5.
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.
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.
胰腺癌或胰腺导管腺癌（PDAC）是最具破坏性的癌症类型之一，其 5 年生存率仅为 9%。PDAC 是男女癌症相关死亡的主要原因之一。表观遗传改变可能导致肿瘤抑制基因的抑制，而 DNA 甲基化是一种主要的表观遗传修饰。DNA 甲基转移酶 1（DNMT1）是在细胞复制过程中维持 DNA 甲基化模式所必需的。越来越多的证据表明 DNMT1 在包括 PDAC 在内的各种恶性肿瘤中具有致癌作用。
本文介绍并讨论了 DNMT1 在 PDAC 中的表达谱、致癌作用、调控因子和抑制剂。与非癌性胰腺导管相比，DNMT1 在 PDAC 病例中过度表达，并且其表达从癌前病变到 PDAC 逐渐增加。DNMT1 通过肿瘤抑制基因启动子的超甲基化在抑制 PDAC 细胞分化和促进其增殖、迁移和侵袭以及诱导 PDAC 癌症干细胞的自我更新能力方面发挥致癌作用，这些基因包括细胞周期蛋白依赖性激酶抑制剂（如 p14、p15、p16、p21 和 p27）、上皮-间充质转化抑制剂（如 E-钙粘蛋白）和肿瘤抑制 miRNA（如 miR-148a、miR-152 和 miR-17-92 簇）。临床前研究表明，新型非核苷 DNMT1 抑制剂对 PDAC 细胞具有强大的抑制作用。最后，目前正在进行 DNMT1 抑制剂（阿扎胞苷、地西他滨和 guadecitabine）在 PDAC 患者中的 I/II 期临床试验，这些抑制剂有可能使 PDAC 对化疗和免疫检查点阻断治疗敏感。
