Faculty, Staff and Student Publications
Publication Date
6-1-2025
Journal
NAR Cancer
DOI
10.1093/narcan/zcaf018
PMID
40433167
PMCID
PMC12107434
PubMedCentral® Posted Date
5-27-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Humans, DNA (Cytosine-5-)-Methyltransferases, Lung Neoplasms, DNA Methyltransferase 3B, DNA (Cytosine-5-)-Methyltransferase 1, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, DNA Methylation, Pyridines, Cell Proliferation, Cell Survival, A549 Cells, Promoter Regions, Genetic, Up-Regulation
Published Open-Access
yes
Recommended Citation
Chen, Qin; Hardikar, Swanand; Kondo, Kimie; et al., "GSK-3484862, a DNMT1 Degrader, Promotes DNMT3B Expression in Lung Cancer Cells" (2025). Faculty, Staff and Student Publications. 4295.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4295
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