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.

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

“…Additionally, Tp63 was shown to regulate expression of FZD7 and to enhance Wnt signaling in mammary normal and malignant tissue (48). A putative crosstalk between Wnt/b catenin pathway and ΔNp63, the TP63 isoform lacking the N-terminus domain, was reported in skin, hair follicles, mammary glands and limb buds during development (50). We observed a similar direct and strong correlation between TP63 and FZD7 expression levels in OC cells, supporting that expression of this receptor may be regulated by this transcription factor.…”

Dishevelled: A masterful conductor of complex Wnt signals

“…In 2014, DVL-1 was shown to bind to a 2kb region upstream of the transcription start site of the Frizzled 7 gene in T-47D breast cancer cells. Interestingly, this binding was shown to be diminished with SIRT1/2 pharmacological inhibition, suggesting that DVL-1 protein levels and promoter occupancy could be regulated by at least one type of lysine deacetylase [19]. In addition, DVL was shown to modulate Wnt signaling by interacting with nuclear proteins such as HIPK1(Homeodomain-interacting protein kinase 1), xNET1 (Xenpous nucleotide exchange factor), and FOXKs (Forkhead box transcription factor) [20–22].…”

MicroRNA-27b suppresses Helicobacter pylori-induced gastric tumorigenesis through negatively regulating Frizzled7

“…Frizzled7 (FZD7) is a critical receptor for the WNT/β-catenin signaling pathway (16,17). Various studies have reported that FZD7 plays an important role in many types of human cancers, including renal cell carcinoma (18), cervical cancer (19), ovarian cancer (17), breast cancer (20), colon cancer (21), and hepatocellular carcinoma (22). It participates in carcinogenesis mainly through promoting the activation of the WNT/β-catenin signaling pathway.…”