Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng
{"title":"GSK-3484862, a DNMT1 degrader, promotes <i>DNMT3B</i> expression in lung cancer cells.","authors":"Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng","doi":"10.1093/narcan/zcaf018","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>DNMT3B</i> expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting <i>DNMT3B</i> in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces demethylation at <i>DNMT3B</i> regulatory elements including a candidate enhancer located ∼10 kb upstream of the <i>DNMT3B</i> transcription start site, as well as at the promoter of <i>TERT</i> (telomerase reverse transcriptase), a potential activator of <i>DNMT3B</i> expression. These demethylation events correlate with upregulation of <i>DNMT3B</i> expression. These findings suggest that combining inhibitors targeting DNMT1, the maintenance methyltransferase, with those targeting DNMT3A/3B, the <i>de novo</i> methyltransferases, or using pan-DNMT inhibitors, could enhance anticancer efficacy and reduce resistance.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf018"},"PeriodicalIF":3.4000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107434/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"NAR cancer","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/narcan/zcaf018","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.