Development of resistance to platinum (Pt) in ovarian cancer (OC) remains a major clinical challenge. Here we focused on identifying epitranscriptomic modifications linked to Pt resistance. FTO is a N6-methyladenosine (m6A) RNA demethylase recently described by us as a tumor suppressor in OC. We hypothesized that FTO induced removal of m6A marks regulates the cellular response of OC cells to Pt and is linked to the development of resistance. To study the involvement of FTO in the cellular response to Pt, we used OC cells in which FTO was knocked down (KD) via shRNA or overexpressed and Pt-resistant (Pt-R) models derived through repeated cycles of exposure to Pt. We found that FTO was significantly downregulated in Pt-R vs. sensitive OC cells. Forced expression of FTO, but not of mutant FTO, increased sensitivity to Pt in vitro and in vivo (p<0.05). Increased numbers of -H2AX foci, measuring DNA double strand breaks, and increased apoptosis were observed after exposure to Pt in FTO overexpressing vs. control cells. Through integrated RNA-sequencing and MeRIP-sequencing, we identified and validated the enzyme nicotinamide N-methyltransferase (NNMT), as a new FTO target linked to Pt response. NNMT was upregulated and demethylated in FTO overexpressing cells. Treatment with an NNMT inhibitor or NNMT knockdown restored sensitivity to Pt in FTO overexpressing cells. Our results support a new function for FTO-dependent m6A RNA modifications in regulating the response to Pt through NNMT, a newly identified RNA methylated gene target.

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