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. N 6 -methyladenosine (m 6 A) is the most abundant chemical modification of mRNA, yet the role of m 6 A modification in PARPi resistance has not previously been explored. Here, we show that m 6 A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/b-catenin pathway in BRCA-mutated EOC cells. Global m 6 A profile revealed a significant increase in m 6 A modification in FZD10 mRNA, which correlated with increased FZD10 mRNA stability and an upregulation of the Wnt/b-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/b-catenin sensitizes resistant cells to PARPi. Mechanistically, downregulation of m 6 A demethylases FTO and ALKBH5 was suffi-cient to increase FZD10 mRNA m 6 A modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/b-catenin showed synergistic suppression of PARPi-resistant cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m 6 A contributes to PARPi resistance in BRCA-deficient EOC cells by upregulating the Wnt/b-catenin pathway via stabilization of FZD10. They also suggest that inhibition of the Wnt/b-catenin pathway represents a potential strategy to overcome PARPi resistance.Significance: These findings elucidate a novel regulatory mechanism of PARPi resistance in EOC by showing that m 6 A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/b-catenin pathway.

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

“…FZD7(+) cells were shown to proliferate more robustly as spheres, to express higher levels of stemness associated TFs, Sox2 and Nanog, and be enriched in a stemness transcriptomic signature. Interestingly, a related receptor, FZD10, was recently reported as a marker of resistance to PARP inhibitors (42). Thus, it is likely that activation of the Wnt pathway through activation of one or more of the FZD receptors is linked to resistance to DNA-damaging agents.…”

Wnt Signaling and Drug Resistance in Cancer

“…Although this protective effect has been attributed to the downstream effectors of Wnt/b-catenin signaling such as survivin in one study, more generally the underlining mechanism still remains unclear (Watson et al, 2010;Gao et al, 2013;Nagano et al, 2013;Emons et al, 2017). Two recent studies found that elevated Wnt signaling enhanced the DNA damage repair and thereby conferred resistance to the PARP inhibitor olaparib in ovarian cancers (Fukumoto et al, 2019;Yamamoto et al, 2019). This mechanism could also protect cancer cells from DNA damage caused by other conventional chemo agents or radiation.…”

“…Wnt/b-catenin signaling mediated resistance to PARP inhibition in ovarian cancer due in part to upregulation of DNA damage repair. Inhibition of b-catenin signaling reverted resistance to olaparib in ovarian cancer xenografts (Fukumoto et al, 2019;Yamamoto et al, 2019). Vismodegib (Hedgehog signaling inhibitor)…”

N6-Methyladenosine: A Novel RNA Imprint in Human Cancer

“…However, in epithelial ovarian cancers (EOC) with BRCA mutation, downregulation of FTO confers resistance to PARP inhibitors such as Olaparib, with m 6 A enrichment in 3 ′ -UTR regions of FZD10 and increased mRNA stability (61). FZD10 positively upregulates Wnt/β-catenin pathway and further promotes activity of homologous recombination.…”

“…Similar to FTO in BRCA-mutated EOC, expression of ALKBH5 is also inhibited, which activates Wnt/β-catenin pathway via stabilizing FZD10 mRNA and renders cell resistance to Olaparib (61).…”