FTO-Dependent N6-Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self-Renewal by Blocking cAMP Signaling

Published on Aug 15, 2020in Cancer Research9.727
· DOI :10.1158/0008-5472.CAN-19-4044
Hao Huang25
Estimated H-index: 25
(NU: Northwestern University),
Hao Huang31
Estimated H-index: 31
(NU: Northwestern University)
+ 8 AuthorsDaniela Matei59
Estimated H-index: 59
(NU: Northwestern University)
Sources
Abstract
N6-Methyladenosine (m6A) is the most abundant modification of mammalian messenger RNAs (mRNA). 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 3'UTR and the mRNA stability of two phosphodiesterase genes (PDE1C and PDE4B), FTO augmented second messenger 3', 5'-cyclic adenosine monophosphate (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.
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