Chen Qin, Hardikar Swanand, Kondo Kimie, Dai Nan, Jr Ivan R Corrêa, Yu Meigen, Estecio Marcos R, Zhang Xing, Chen Taiping, Cheng Xiaodong
Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
New England Biolabs, Inc., Ipswich, MA 01938, United States.
NAR Cancer. 2025 May 27;7(2):zcaf018. doi: 10.1093/narcan/zcaf018. eCollection 2025 Jun.
DNA methylation alterations, including hypermethylation and silencing of tumor suppressor genes, contribute to cancer formation and progression. The FDA-approved nucleoside analogs azacytidine and decitabine are effective demethylating agents for hematologic malignancies but their general use has been limited by their toxicity and ineffectiveness against solid tumors. GSK-3484862, a dicyanopyridine-containing, DNMT1-selective inhibitor and degrader, offers a promising lead for developing novel demethylating therapeutics. Here, we demonstrate that GSK-3484862 treatment upregulates expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces demethylation at regulatory elements including a candidate enhancer located ∼10 kb upstream of the transcription start site, as well as at the promoter of (telomerase reverse transcriptase), a potential activator of expression. These demethylation events correlate with upregulation of expression. These findings suggest that combining inhibitors targeting DNMT1, the maintenance methyltransferase, with those targeting DNMT3A/3B, the methyltransferases, or using pan-DNMT inhibitors, could enhance anticancer efficacy and reduce resistance.
DNA甲基化改变，包括肿瘤抑制基因的高甲基化和沉默，促进了癌症的形成和进展。美国食品药品监督管理局（FDA）批准的核苷类似物阿扎胞苷和地西他滨是治疗血液系统恶性肿瘤的有效去甲基化药物，但它们的普遍应用受到毒性和对实体瘤无效的限制。GSK-3484862是一种含二氰基吡啶的DNMT1选择性抑制剂和降解剂，为开发新型去甲基化疗法提供了有前景的线索。在此，我们证明GSK-3484862处理可上调肺癌细胞系（A549和NCI-H1299）中的表达。在NCI-H1299中破坏可使这些细胞对GSK-3484862敏感，增强其对细胞活力和生长的抑制作用。GSK-3484862处理可诱导在调控元件处发生去甲基化，这些调控元件包括位于转录起始位点上游约10 kb处的一个候选增强子，以及在（端粒酶逆转录酶）启动子处的去甲基化，是表达的潜在激活剂。这些去甲基化事件与表达的上调相关。这些发现表明，将靶向维持甲基转移酶DNMT1的抑制剂与靶向从头甲基转移酶DNMT3A/3B的抑制剂联合使用，或使用泛DNMT抑制剂，可增强抗癌疗效并降低耐药性。
