GSK-3484862, a DNMT1 degrader, promotes DNMT3B expression in lung cancer cells.

IF 3.4 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2025-05-27 eCollection Date: 2025-06-01 DOI:10.1093/narcan/zcaf018
Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng
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引用次数: 0

Abstract

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 DNMT3B expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting DNMT3B in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces demethylation at DNMT3B regulatory elements including a candidate enhancer located ∼10 kb upstream of the DNMT3B transcription start site, as well as at the promoter of TERT (telomerase reverse transcriptase), a potential activator of DNMT3B expression. These demethylation events correlate with upregulation of DNMT3B expression. These findings suggest that combining inhibitors targeting DNMT1, the maintenance methyltransferase, with those targeting DNMT3A/3B, the de novo methyltransferases, or using pan-DNMT inhibitors, could enhance anticancer efficacy and reduce resistance.

GSK-3484862是一种DNMT1降解剂,可促进肺癌细胞中DNMT3B的表达。
DNA甲基化改变,包括肿瘤抑制基因的超甲基化和沉默,有助于癌症的形成和进展。fda批准的核苷类似物阿扎胞苷和地西他滨是治疗血液恶性肿瘤的有效去甲基化药物,但由于它们的毒性和对实体肿瘤的无效,它们的普遍使用受到限制。GSK-3484862是一种含二氰吡啶的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希望的先导。在这里,我们证明GSK-3484862治疗上调DNMT3B在肺癌细胞系(A549和NCI-H1299)中的表达。破坏NCI-H1299中的DNMT3B可使这些细胞对GSK-3484862增敏,增强GSK-3484862对细胞活力和生长的抑制作用。GSK-3484862处理诱导DNMT3B调控元件的去甲基化,包括位于DNMT3B转录起始位点上游约10 kb的候选增强子,以及TERT(端粒酶逆转录酶)的启动子,TERT是DNMT3B表达的潜在激活剂。这些去甲基化事件与DNMT3B表达上调相关。这些发现表明,靶向维持性甲基转移酶DNMT1的抑制剂与靶向新甲基转移酶DNMT3A/3B的抑制剂联合使用,或使用泛dnmt抑制剂,可以增强抗癌疗效并降低耐药性。
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来源期刊
CiteScore
6.90
自引率
0.00%
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审稿时长
13 weeks
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