N6-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance
Abstract
Despite the high initial response rates to PARP inhibitors (PARPi) in BRCA-mutated epithelial ovarian cancers (EOC), PARPi 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 PARPi resistance has not previously been explored. Here, we show that m6A modification of FZD10 mRNA contributes to PARPi 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 PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 was sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/β-catenin showed synergistic suppression of PARPi-resistant cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m6A contributes to PARPi 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 PARPi resistance.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 01, 2019
- Source ID
- 10.1158/0008-5472.can-18-3592
Entities
People
- Andrew V Kossenkov
- Hengrui Zhu
- Louise C. Showe
- Nail Fatkhutdinov
- Pingyu Liu
- Rugang Zhang
- Sergey Karakashev
- Shuai Wu
- Stephanie Jean
- Takeshi Fukumoto
- Timothy Nacarelli
Organizations
- National Institutes of Health
- United States Department of Defense
- University of Pennsylvania
- Wistar Institute