Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0028754 (
obesity
)
124,988
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
N
6
-Methyladenosine (m
6
A) 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 m
6
A 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 m
6
A mapping analysis revealed significant transcriptomic changes associated with
FTO
overexpression and m
6
A loss involving stem cell signaling, RNA transcription, and mRNA splicing pathways. By reducing m
6
A 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 m
6
A RNA modifications in the regulation of cyclic AMP signaling involved in stemness and
tumor initiation
.
...
PMID:FTO-Dependent
N
6
-Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self-Renewal by Blocking cAMP Signaling. 3260 6
High-fat diet (HFD)-induced
obesity
is associated with increased cancer risk. Long-term feeding with HFD increases the concentration of the saturated fatty acid palmitic acid (PA) in the hypothalamus. We previously showed that, in hypothalamic neuronal cells, exposure to PA inhibits the autophagic flux, which is the whole autophagic process from the synthesis of the autophagosomes, up to their lysosomal fusion and degradation. However, the mechanism by which PA impairs autophagy in hypothalamic neurons remains unknown. Here, we show that PA-mediated reduction of the autophagic flux is not caused by lysosomal dysfunction, as PA treatment does not impair lysosomal pH or the activity of cathepsin B.Instead, PA dysregulates autophagy by reducing autophagosome-lysosome fusion, which correlates with the swelling of endolysosomal compartments that show areduction in their dynamics. Finally, because lysosomes undergo constant dynamic regulation by the small Rab7 GTPase, we investigated the effect of PA treatment on its activity. Interestingly, we found PA treatment altered the activity of Rab7. Altogether, these results unveil the cellular process by which PA exposure impairs the autophagic flux. As impaired autophagy in hypothalamic neurons promotes
obesity
, and balanced autophagy is required to inhibit malignant transformation, this could affect
tumor initiation
, progression, and/or response to therapy of
obesity
-related cancers.
...
PMID:Palmitic acid reduces the autophagic flux in hypothalamic neurons by impairing autophagosome-lysosome fusion and endolysosomal dynamics. 3294 43
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