N⁶-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance.

Despite the high initial response rates to inhibitors in BRCA-mutated epithelial ovarian cancers (EOC), resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N⁶-methyladenosine (m⁶A) is the most abundant chemical modification of mRNA, yet the role of m⁶A modification in Pduanyu37i resistance has not previously been explored. Here, we show that m⁶A modification of FZD10 mRNA contributes to Pduanyu37i resistance by upregulating the Wnt/β-catenin pathway in BRCA-mutated EOC cells. Global m⁶A profile revealed a significant increase in m⁶A modification in FZD10 mRNA, which correlated with increased FZD10 mRNA stability and an upregulation of the Wnt/β-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/β-catenin sensitizes resistant cells to Mechanistically, downregulation of m⁶A demethylases FTO and ALKBH5 was sufficient to increase FZD10 mRNA m⁶A modification and reduce Pduanyu37i sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of Pduanyu37 and Wnt/β-catenin showed synergistic suppression of cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m⁶A contributes to Pduanyu37i resistance in BRCA-deficient EOC cells by upregulating the Wnt/β-catenin pathway via stabilization of FZD10. They also suggest that inhibition of the Wnt/β-catenin pathway represents a potential strategy to overcome Pduanyu37i resistance. SIGNIFICANCE: These findings elucidate a novel regulatory mechanism of Pduanyu37i resistance in EOC by showing that m⁶A modification of FZD10 mRNA contributes to Pduanyu37i resistance in BRCA-deficient EOC cells via upregulation of Wnt/β-catenin pathway.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}