Downregulation of ASPP2 improves hepatocellular carcinoma cells survival via promoting BECN1-dependent autophagy initiation.

Abstract

Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, as a molecular regulator of starvation-induced autophagy in hepatocellular carcinoma (HCC). ASPP2 expression is associated with an autophagic response upon nutrient deprivation and downregulation of ASPP2 facilitates autophagic flux, whereas overexpression of ASPP2 blocks this starvation-induced autophagy in HCC cells. Mechanistically, ASPP2 inhibits autophagy through regulating BECN1 transcription and formation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) complex. Firstly, ASPP2 inhibits p65/RelA-induced transcription of BECN1, directly by an ASPP2-p65/RelA-IκBα complex which inhibits phosphorylation of IκBα and the translocation of p65/RelA into the nucleus. Secondly, ASPP2 binds to BECN1, leading to decreased binding of PIK3C3 and UV radiation resistance-associated gene (UVRAG), and increased binding of Rubicon in PIK3C3 complex. Downregulation of ASPP2 enhances the pro-survival and chemoresistant property via autophagy in HCC cells in vitro and in vivo. Decreased ASPP2 expression was associated with increased BECN1 and poor survival in HCC patients. Therefore, ASPP2 is a key regulator of BECN1-dependent autophagy, and decreased ASPP2 may contribute to tumor progression and chemoresistance via promoting autophagy.

• Authors: Rui Chen, Hao Wang, Beibei Liang, Guoke Liu, Min Tang, Rongjie Jia, Xiaoyu Fan, Wei Jing, Xuyu Zhou, Huajing Wang, Yang Yang, Huafeng Wei, Bohua Li, Jian Zhao
• Journal: Cell death & disease (Cell Death Dis) Vol. 7 Issue 12 Pg. e2512 (12 08 2016) ISSN: 2041-4889 [Electronic] England
• PMID: 27929538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• TP53BP2 protein, human
• Transcription Factor RelA

Topics

• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy
• Beclin-1 (genetics, metabolism)
• Carcinoma, Hepatocellular (metabolism, pathology, surgery)
• Cell Line, Tumor
• Cell Survival
• Down-Regulation
• Drug Resistance, Neoplasm
• Gene Silencing
• Humans
• Immunoprecipitation
• Liver Neoplasms (metabolism, pathology, surgery)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Protein Binding
• Transcription Factor RelA (metabolism)
• Transcriptional Activation (genetics)