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G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1

ABSTRACT: Treatment of non-small cell lung cancer (NSCLC) patients has greatly improved with recent therapeutic strategies but many patients do not benefit from them. Therefore, new treatment strategies are highly needed. Here we have assessed the antitumor efficacy of co-targeting G9 and DNMT1 enzymes and its potential as a cancer-drug sensitizer. We found co-expression and overexpression of G9a and DNMT1 in NSCLC, in association with poor prognosis. G9a/DNMT1 co-targeting with the drug CM-272 reduced proliferation and increased apoptosis in a panel of human and murine NSCLC cell lines. Moreover, reprogramming of the transcriptome of these cells to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib) and epigenetic therapy (vorinostat) was observed. In vivo, CM-272 decreased tumor volume in human and murine cell-derived cancer models, an effect synergistically enhanced by cisplatin. Expression of SCARA5 and AOX1 was induced by CM-272 and both proteins were found to be essential for the antiproliferative response, as gene silencing reduced cytotoxicity. Expression of SCARA5 and AOX1 was positively correlated among themselves and inversely correlated with that of G9a and DNMT1, in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was found as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Therefore, we demonstrate that G9a/DNMT1-co-targeting is a promising strategy to enhance the effect of cancer-drugs and that SCARA5 methylation could be used as a non-invasive biomarker to monitor tumor evolution.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273400 | GEO | 2026/07/15

REPOSITORIES: GEO

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