SIRT6 Is a Target of Regulation by UBE3A That Contributes to Liver Tumorigenesis in an ANXA2-Dependent Manner

Abstract

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor-suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of was sufficient to stabilize SIRT6 and to epigenetically repress, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential, and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease. These findings provide mechanistic insights into regulation of the tumor suppressive sirtuin SIRT6 and its implications for the development of hepatocellular carcinoma. .

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma

“…F). ANXA2 is upregulated in a variety of cancers, including HCC . Inhibition of ANXA2 decreases migration and invasion of HCC cells and is a putative biomarker for HCC .…”

“…ANXA2 is upregulated in a variety of cancers, including HCC. (36) Inhibition of ANXA2 decreases migration and invasion of HCC cells (37) and is a putative biomarker for HCC. (38) Taken together, the integrated approach used here resulted in identification of loci that have been firmly linked to hepatocarcinogenesis (e.g., ANXA2) and that represent functionally relevant epigenetically regulated genes (COMT and FMO3).…”

S100A11 functions as novel oncogene in glioblastoma via S100A11/ANXA2/NF‐κB positive feedback loop

“…The molecular mechanisms of S100A11 by which promote the development and progression of GBM is unknown. ANXA2 is a calcium‐dependent phospholipid‐binding protein . ANXA2 is overexpressed in various tumours, including breast cancer, pancreatic cancer, ESCC and glioma, which plays important roles in tumour progression by regulating cell growth, apoptosis, invasion and tumour neovascularization .…”

“…ANXA2 is a calcium-dependent phospholipid-binding protein. 33 ANXA2 is overexpressed in various tumours, including breast cancer, pancreatic cancer, ESCC and glioma, which plays important roles in tumour progression by regulating cell growth, apoptosis, invasion and tumour neovascularization. 14 Calcium can trigger S100A11-ANXA2 interaction in repair cell membrane.…”

Long non‐coding RNA LUCAT1 promotes tumourigenesis by inhibiting ANXA2 phosphorylation in hepatocellular carcinoma

“…Our results revealed that LUCAT1 bound to ANXA2 specifically. Annexin A2 is proved to be implicated in various cancers, including HCC . For example, Zhang et al reported that shRNA‐mediated silencing of ANXA2 suppresses the invasion, migration and tumourigenic potential of hepatoma cells and may thus be utilized as a target of future molecular therapies .…”