DNA hypermethylation drives BVES-mediated autophagy to promote cisplatin resistance in lung adenocarcinoma.

Aberrant DNA methylation induces abnormal expression of drug-resistance genes, promoting drug resistance. This study identified specific DNA methylation patterns driving LUAD chemoresistance and explored their mechanisms. Blood vessel epicardial substance (BVES) expression and methylation were analyzed by using TCGA and MethylMix. Primers for the BVES CpG island were designed with MethPrimer. Pathways for BVES were analyzed by gene set enrichment analysis. Methylation-specific quantitative PCR detected the levels of BVES methylation. Quantitative reverse transcription polymerase chain reaction evaluated BVES expression, and western blot analyzed the expression of BVES, LC3, and P62. The cell counting kit-8 was used to determine IC50 and cell viability. Cell proliferation assessment was achieved by colony formation assay, and apoptosis was evaluated by flow cytometry. LC3 expression was observed through immunofluorescence. The findings displayed hypermethylation of BVES in LUAD tissues and cells, which was further elevated in the setting of cisplatin (DDP) resistance. The overexpression of BVES in A549/DDP cells substantially repressed their proliferation in response to DDP and markedly amplified the apoptotic effects induced by DDP. In the rescue experiments, autophagy stimulants effectively eliminated the DDP sensitivity enhancement caused by BVES overexpression in A549/DDP cells. In vivo assays confirmed that BVES overexpression suppressed autophagy and augmented the therapeutic impact of DDP. BVES hypermethylation, through the promotion of autophagy, reinforces resistance to DDP in LUAD. This study indicates that repressing BVES methylation and upregulating its expression may be a strategic way to combat cisplatin resistance in LUAD patients.