SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling

Abstract

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.+ -dependent histone deacetylase (HDAC) that regulates a very broad and complex array of physiological processes. As such, it has been the source of some controversy, as it has been difficult to reconcile the role it plays in the coordination of cellular responses and gene expression in both normal and pathophysiological settings. For example, SIRT1 has been shown to inhibit the maturation of preadipocytes (1, 2), antagonize p53-dependent apoptosis in response to stress (3, 4), and promote chemoresistance to conventional chemotherapeutic agents (5, 6), and is associated with microsatellite instability and CpG island methylator phenotype in human colorectal cancer (7). Furthermore, reports demonstrate that SIRT1 coordinates diverse metabolic responses to changes in nutrient availability (8), regulates autophagy (9), and controls key stages of spermatogenesis and germ stem cell proliferation and function (10, 11). Given the complex influence of SIRT1 on cell-fate decisions in multiple physiological settings, it is reasonable to anticipate that SIRT1 regulates one or more signaling networks recognized for their influence on these diverse cellular and organismal responses.It is well-established that Wnt signaling, likewise, regulates diverse processes such as adipogenesis (12), tumorigenesis (13), and stem cell pluripotency (14, 15). When Wnt ligands are present, they transmit signals through specific Frizzled (Fzd) or Fzd/LRP5/6 coreceptor complexes (16). This signal is then propagated via Dishevelled (Dvl) proteins that will direct canonical (β-catenindependent) or noncanonical (β-catenin-independent) signaling (17). Most of the mechanistic insights into Wnt signaling...

Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing β-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors

“…However, the expression of Sost was unaffected in the mice of the present work, suggesting that Sost could not be responsible for the bone phenotype. In other cell types, Sirt1 can stimulate Wnt signaling via regulating Dishevelled proteins (39) and by promoting epigenetic silencing of Wnt antagonists (40). It remains unknown whether these alternative mechanisms of Wnt signaling potentiation by Sirt1 play a role in osteoprogenitors.…”

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

“…Hence, SIRT1 activation downregulated SIPS through FOXO3/p21 pathway, thereby protecting against emphysema. In addition to FOXO3, recent studies have demonstrated the involvement of other developmental and senescence-related genes, such as Wnt/β-catenin, Notch, Klotho, senescence marker protein-30, and Werner syndrome protein, in the development of emphysema (55)(56)(57)(58)(59)(60). However, it remains to be seen whether SIRT1 targets these genes in response to CS exposure.…”

ATG4B promotes colorectal cancer growth independent of autophagic flux

“…7 Aberrant expression of WNT activates its signaling through autocrine mechanisms in colorectal sarcomas and sarcoma cell lines. [30][31][32] To examine the involvement of ATG4B-mediated autophagy on WNT signaling and tumor proliferation, we used human colorectal cancer HCT116 cells, a WNT3A expressed and a CTNNB1/β-catenin (catenin [cadherin-associated protein], β 1, 88 kDa)-mutated cell line that is highly responsive to WNT signaling. 31,33 Besides degradation of SQSTM1, protein levels of both DVL2 and CCND1 were decreased in colorectal cancer HCT116 cells silenced with ATG4B siRNA, and mRNA level of CCND1 was reduced in the ATG4B-knockdown cells (Fig.…”