HRD1-mediated PTEN degradation promotes cell proliferation and hepatocellular carcinoma progression

Cell Signal. 2018 Oct:50:90-99. doi: 10.1016/j.cellsig.2018.06.011. Epub 2018 Jun 27.

Abstract

The tyrosine phosphatases family member PTEN is a tumor suppressor which is widely expressed throughout the body and is involved in a variety of biological functions. PTEN is known to be frequently mutated or downregulated in human cancers. However, the underlying molecular mechanism remains largely unknown. Here, using a proteomic approach, we identified the E3 ubiquitin ligase HRD1, which was previously reported to be involved in endoplasmic reticulum associated degradation (ERAD), as one of the PTEN-interacting proteins. We also found that HRD1 promoted PTEN degradation by positively regulating its ubiquitination. In addition, suppression of HRD1 expression resulted in the inhibition of the growth, migration and invasion of hepatocellular carcinoma in vitro and in vivo. Finally, we detected a negative correlation between HRD1 and PTEN expression in human hepatocellular carcinoma. From these results we propose a novel molecular mechanism of HRD1 to promote hepatocellular tumorigenesis via PTEN inactivation. We conclude that targeting HRD1 may represent a new therapeutic strategy for PTEN-loss hepatocellular carcinoma.

Keywords: HCC; HRD1; PTEN; Ubiquitination.

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics*
  • Disease Progression
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum-Associated Degradation / genetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • PTEN Phosphohydrolase / genetics*
  • Proteomics / methods
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitination / genetics

Substances

  • SYVN1 protein, human
  • Ubiquitin-Protein Ligases
  • PTEN Phosphohydrolase
  • PTEN protein, human