Abstract
N6-Methyladenosine (m6A) is the most abundant modification of mammalian mRNAs. RNA methylation fine tunes RNA stability and translation, altering cell fate. The fat mass- and obesity-associated protein (FTO) is an m6A demethylase with oncogenic properties in leukemia. Here, we show that FTO expression is suppressed in ovarian tumors and cancer stem cells (CSC). FTO inhibited the self-renewal of ovarian CSC and suppressed tumorigenesis in vivo, both of which required FTO demethylase activity. Integrative RNA sequencing and m6A mapping analysis revealed significant transcriptomic changes associated with FTO overexpression and m6A loss involving stem cell signaling, RNA transcription, and mRNA splicing pathways. By reducing m6A levels at the 30UTR and the mRNA stability of two phosphodiesterase genes (PDE1C and PDE4B), FTO augmented second messenger 30, 50-cyclic adenosine mono-phosphate (cAMP) signaling and suppressed stemness features of ovarian cancer cells. Our results reveal a previously unappreciated tumor suppressor function of FTO in ovarian CSC mediated through inhibition of cAMP signaling.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3200-3214 |
| Number of pages | 15 |
| Journal | Cancer Research |
| Volume | 80 |
| Issue number | 16 |
| DOIs | |
| State | Published - Aug 15 2020 |
Funding
M. Kandpal reports grants from NIH (funding from 5R01LM011297-06, PI: Ramana Davuluri) during the conduct of the study. J. Chen reports other grants from Genovel Biotech Corp (scientific founder of the company) outside the submitted work. R.V. Davuluri reports grants from NIH (R01LM011297 grant from NLM) during the conduct of the study. D. Matei reports personal fees from Radius Inc. (consultant), GSK (consultant), Astra Zeneca (consultant), and GOG Foundation (mentor/consultant) outside the submitted work. No potential conflicts of interest were disclosed by the other authors. This research was supported by the U.S. Department of Veterans Affairs (I01 BX000792-06), NCI (R01-CA224275), and the Diana Princess of Wales endowed Professorship from the Robert H. Comprehensive Cancer Center (to D. Matei). Tumor specimens were procured through the Tissue Pathology Core, sequencing was performed in the NUSeq Core, and flow cytometry analyses were performed in the Flow Cytometry Core Facility supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This research was supported in part through the computational resources and staff contributions provided for the Quest high performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. J. Chen is supported by NIH R01 CA214965. We thank Dr. Marcus Peter for valuable comments.
ASJC Scopus subject areas
- Oncology
- Cancer Research
