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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.
Highlights
Autophagy is a lysosomal-dependent cellular degradation process, in which the cell self-digests its proteins and organelles and generates nutrients and energy to maintain essential cellular activities following nutrient starvation.[1]
Autophagy plays a critical role in the pathogenesis of diverse diseases, such as neuronal degeneration, aging, and cancer.[2,3,4,5,6]
Decreasing analysis predicted that TP53BP2 (ASPP2) protein level correlated with increased conversion of LC3I to LC3II in HepG2 and hepatocellular carcinoma (HCC)-LM3 liver cancer cells following nutrient deprivation (Figure 1a)
Summary
Autophagy is a lysosomal-dependent cellular degradation process, in which the cell self-digests its proteins and organelles and generates nutrients and energy to maintain essential cellular activities following nutrient starvation.[1]. ASPP2 is a haploin-sufficient tumor suppressor, and aberrant expression of ASPP2 has been found in a variety of human cancers, including lung cancer, breast cancer, and leukemia.[18] Our previous study found that ASPP2 is downregulated by DNA methylation in HCC.[19] Recent studies have shown that ASPP2 inhibits RAS-induced autophagic activity to dictate the cellular response to RAS.[20] it remains unknown whether downregulation of ASPP2 is involved in the regulation of autophagy in HCC. We provide evidence that downregulation of ASPP2 may contribute to tumor progression and chemoresistance via promoting BECN1-dependent autophagy in HCC
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