SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling.
Sirtuin 1 (SIRT1) is a class III histone deacetylase that deacetylates histone and nonhistone proteins to regulate gene transcription and protein function. Because SIRT1 regulates very diverse responses such as apoptosis, insulin sensitivity, autophagy, differentiation, and stem cell pluripotency, it has been a challenge to reconcile how it orchestrates such pleiotropic effects. Here we show that SIRT1 serves as an important regulator of Wnt signaling. We demonstrate that SIRT1 loss of function leads to a significant decrease in the levels of all three Dishevelled (Dvl) proteins. Furthermore, we demonstrate that SIRT1 and Dvl proteins complex in vivo and that inhibition of SIRT1 leads to changes in gene expression of Wnt target genes. Finally, we demonstrate that Wnt-stimulated cell migration is inhibited by a SIRT1 inhibitor. Because the three mammalian Dvl proteins serve as key messengers for as many as 19 Wnt ligands, SIRT1-mediated regulation of Dvl proteins may explain the diverse physiological responses observed in different cellular contexts. Previously, SIRT1 had only been shown to mediate the epigenetic silencing of Wnt antagonists. In contrast, here we report that SIRT1 regulates Dvl protein levels and Wnt signaling in several cellular contexts. These findings demonstrate that SIRT1 is a regulator of transient and constitutive Wnt signaling.
Holloway
Kimberly R
KR
Department of Molecular and Cellular Physiology, School of Medicine, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Calhoun
Tara N
TN
Saxena
Madhurima
M
Metoyer
Cheynita F
CF
Kandler
Ethan F
EF
Rivera
Chantal A
CA
Pruitt
Kevin
K
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D000072261:Dishevelled Proteins; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D010750:Phosphoproteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; C447939:SIRT1 protein, human; D056564:Sirtuin 1