FTO-Dependent N6-Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self-Renewal by Blocking cAMP Signaling
| Autor: | Hao Huang, Yanrong Ji, Guangyuan Zhao, Jianjun Chen, Edward J. Tanner, Manoj Kandpal, Anusha Chaparala, Yinu Wang, Ramana V. Davuluri, Daniela Matei, Horacio Cardenas |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Messenger RNA endocrine system diseases biology RNA methylation nutritional and metabolic diseases RNA medicine.disease_cause Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Oncology chemistry Cancer stem cell 030220 oncology & carcinogenesis Demethylase activity biology.protein medicine Demethylase N6-Methyladenosine Carcinogenesis |
| Zdroj: | Cancer Research. 80:3200-3214 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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 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. Significance: A new tumor suppressor function of the RNA demethylase FTO implicates m6A RNA modifications in the regulation of cyclic AMP signaling involved in stemness and tumor initiation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|