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.

中文翻译：

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DNMT1作为胰腺癌的治疗靶点：机制和临床意义。

背景

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。表观遗传的改变可能导致肿瘤抑制基因的抑制，而DNA甲基化是表观遗传的主要修饰。DNA甲基转移酶1（DNMT1）是维持细胞复制过程中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的致癌作用。

结论

本文介绍并讨论了DNMT1在PDAC中的表达概况，致癌作用，调节剂和抑制剂。与非癌性胰管相比，DNMT1在PDAC病例中过表达，其表达从肿瘤前病变到PDAC逐渐增加。DNMT1在抑制PDAC细胞分化，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。这些作用是通过肿瘤抑制基因（包括细胞周期蛋白依赖性激酶抑制剂，例如p14，p15，p16，p21和p27）的启动子高度甲基化来实现的），上皮-间质转化抑制因子（例如E-cadherin）和肿瘤抑制miRNA（例如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细胞的效力。最后，目前正在进行PDAC患者中DNMT1抑制剂（阿扎胞苷，地西他滨和瓜地他滨）的I / II期临床试验，这些抑制剂具有使PDAC对化学疗法和免疫检查点封锁疗法敏感的潜力。