O-GlcNAcylation of histone deacetylases 1 in hepatocellular carcinoma promotes cancer progression

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor originating in the liver. Previous studies have indicated that O-GlcNAc transferase (OGT) and histone deacetylase-1 (HDAC1) play important roles in the pathogenesis of HCC. In the present study, we investigated the physical link between OGT and HDAC1. The O-GlcNAcylation of HDAC1 is overexpressed in HCC. We found that HDAC1 has two major sites of O-GlcNAcylation in its histone deacetylase domain. HDAC1 O-GlcNAcylation increases the activated phosphorylation of HDAC1, which enhances its enzyme activity. HDAC1 O-GlcNAc mutants promote the p21 transcription regulation through affecting the acetylation levels of histones from chromosome, and then influence the proliferation of HCC cells. We also found that mutants of O-GlcNAcylation site of HDAC1 affect invasion and migration of HepG2 cells. E-cadherin level is highly up-regulated in HDAC1 O-GlcNAc mutant-treated liver cancer cells, which inhibit the occurrence and development of HCC. Our findings suggest that OGT promotes the O-GlcNAc modification of HDAC1in the development of HCC. Therefore, inhibiting O-GlcNAcylation of HDAC1 may repress the progression of HCC.

Decreasing O-GlcNAcylation affects the malignant transformation of MCF-7 cells via Hsp27 expression and its O-GlcNAc modification

“…This indicates that the regulation of O-GlcNAcylation and its controlling enzymes in various cancer cell lines may be different. However, previous research from our laboratory and others reported that augmentation of O-GlcNAcylation and OGT levels were associated with the malignant phenotypes of most cancers including breast (11,15), colon (12,16,17), liver (18)(19)(20) and prostate (21,22). It is noted that the regulation of O-GlcNAcylation is dynamic and may not be only dependent on the expression levels of its cycling enzymes (OGT and OGA) but also on its enzymatic activities (23).…”

Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms

“…Increased O-GlcNAcylation is observed in various tumors (Caldwell et al, 2010;Ferrer et al, 2014;Ma and Vosseller, 2014;Slawson et al, 2010;Zhu et al, 2012Zhu et al, , 2016, but its contribution to tumorigenesis is not well understood. Identification of Significance Increased O-GlcNAcylation is observed in cancer cells, but its contribution to tumorigenesis is poorly understood.…”

New Insights into the Epigenetics of Hepatocellular Carcinoma

“…Downregulation of CYP2E1 expression in response to deregulated histone modification which resulted in decline in apoptotic potential has been observed in alcohol-associated HCCs [136, 137]. Recent studies suggest that HCC progression can be repressed by inhibition of O-GlcNAcylation [138]. Epigenetic silencing of JMJD5 (jumonji C domain-containing protein 5), another tumor-suppressor gene in HCC pathogenesis, downregulates CDKN1A transcription to promote HCC cell proliferation [139].…”