Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells.
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 deacetylate...
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doaj-6e17022b1bfb4e84915a56127cdf7c062020-11-24T22:16:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0196e9886110.1371/journal.pone.0098861Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells.Glenn E SimmonsSomnath PandeyAna Nedeljkovic-KurepaMadhurima SaxenaAllison WangKevin PruittThe 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.http://europepmc.org/articles/PMC4045932?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Glenn E Simmons Somnath Pandey Ana Nedeljkovic-Kurepa Madhurima Saxena Allison Wang Kevin Pruitt |
spellingShingle |
Glenn E Simmons Somnath Pandey Ana Nedeljkovic-Kurepa Madhurima Saxena Allison Wang Kevin Pruitt Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells. PLoS ONE |
author_facet |
Glenn E Simmons Somnath Pandey Ana Nedeljkovic-Kurepa Madhurima Saxena Allison Wang Kevin Pruitt |
author_sort |
Glenn E Simmons |
title |
Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells. |
title_short |
Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells. |
title_full |
Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells. |
title_fullStr |
Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells. |
title_full_unstemmed |
Frizzled 7 expression is positively regulated by SIRT1 and β-catenin in breast cancer cells. |
title_sort |
frizzled 7 expression is positively regulated by sirt1 and β-catenin in breast cancer cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4045932?pdf=render |
work_keys_str_mv |
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