Hypoxia-induced m6A demethylase ALKBH5 promotes ovarian cancer tumorigenicity by decreasing methylation of the lncRNA RMRP.

Abstract

Ovarian cancer is one of the most lethal and drug-resistant gynecological diseases. Among the various post-transcriptional RNA modifications, N6-methyladenosine (m6A) has been implicated in several malignancies, including breast cancer. Recently, the biological significance of long noncoding RNA (lncRNA) methylation has garnered significant attention. The N6-methyladenosine (m6A) demethylase ALKBH5 (Alkylation Repair Homolog Protein 5) has been shown to promote ovarian cancer development by reducing the methylation of the lncRNA RMRP. In this study, we found that a hypoxic microenvironment induces an increase in ALKBH5 expression in ovarian cancer. Both in vitro and in vivo investigations demonstrated that ALKBH5, which is overexpressed in human ovarian cancer, promotes carcinogenesis. Furthermore, using bioinformatics analysis, we predicted interactions between ALKBH5 and lncRNAs, confirming RMRP as a potential binding lncRNA for ALKBH5. ALKBH5 was found to upregulate RMRP expression via demethylation. Knockdown of RMRP in ovarian cancer cell lines led to a decrease in cell growth and migration. Additionally, we demonstrated that the inhibition of ovarian cancer by ALKBH5 knockdown is partially mediated by RMRP suppression. In conclusion, our findings reveal a novel mechanism in which ALKBH5 promotes ovarian cancer by demethylating the lncRNA RMRP, suggesting its potential as a therapeutic target for the disease.