title: Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells.
abstract: The Wnt signaling pathway is often chronically activated in diverse human tumors, and the Frizzled (FZD) family of receptors for Wnt ligands, are central to propagating oncogenic signals in a β-catenin-dependent and independent manner. SIRT1 is a class III histone deacetylase (HDAC) that deacetylates histone and non-histone proteins to regulate gene transcription and protein function. We previously demonstrated that SIRT1 loss of function led to a significant decrease in the levels of Dishevelled (Dvl) proteins. To further explore this connection between the sirtuins and components of the Wnt pathway, we analyzed sirtuin-mediated regulation of FZD proteins. Here we explore the contribution of sirtuin deacetylases in promoting constitutive Wnt pathway activation in breast cancer cells. We demonstrate that the use of small molecule inhibitors of SIRT1 and SIRT2, and siRNA specific to SIRT1, all reduce the levels of FZD7 mRNA. We further demonstrate that pharmacologic inhibition of SIRT1/2 causes a marked reduction in FZD7 protein levels. Additionally, we show that β-catenin and c-Jun occupy the 7 kb region upstream of the transcription start site of the FZD7 gene, and SIRT1 inhibition leads to a reduction in the occupancy of both β-catenin and c-Jun at points along this region. This work uncovers a new mechanism for the regulation of FZD7 and provides a critical new link between the sirtuins and FZD7, one of the earliest nodal points from which oncogenic Wnt signaling emanates. This study shows that inhibition of specific sirtuins may provide a unique strategy for inhibiting the constitutively active Wnt pathway at the level of the receptor.
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center School of Medicine in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Simmons
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center School of Medicine in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Somnath
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center School of Medicine in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Ana
authors.initials: A
authors.lastname: Nedeljkovic-Kurepa
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center School of Medicine in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Saxena
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center School of Medicine in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Allison
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center School of Medicine in Shreveport, Shreveport, Louisiana, United States of America; The Feist-Weiller Cancer Center, LSU Health Sciences Center School of Medicine in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Pruitt
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011744:Pyrimidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C115810:FZD7 protein, human; D051157:Frizzled Receptors; D009281:Naphthalenes; D011744:Pyrimidinones; D012333:RNA, Messenger; D051176:beta Catenin; C510718:cambinol; D056564:Sirtuin 1; D056565:Sirtuin 2