title: CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing Beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2.
abstract: Apoptosis-stimulating protein of p53-2 (ASPP2) induces apoptosis by promoting the expression of pro-apoptotic genes via binding to p53 or p73; however, the exact mechanisms by which ASPP2 induces apoptotic death in hepatoma cells are still unclear. Here, we show that the transient overexpression of ASPP2 induces autophagic apoptosis in hepatoma cells by promoting p53- or p73-independent C/EBP homologous protein (CHOP) expression. CHOP expression decreases the expression of Bcl-2; this change releases Beclin-1 from cytoplasmic Bcl-2-Beclin-1 complexes and allows it to initiate autophagy. However, transient overexpression of Beclin-1 can induce autophagy but not apoptosis. Our results show that ASPP2 induces the expression of damage-regulated autophagy modulator (DRAM), another critical factor that cooperates with free Beclin-1 to induce autophagic apoptosis. The effect of CHOP on the translocation and sequestration of Bcl-2 in the nucleus, which requires the binding of Bcl-2 to ASPP2, is also critical for ASPP2-induced autophagic apoptosis. Although the role of nuclear ASPP2-Bcl-2 complexes is still unclear, our results suggest that nuclear ASPP2 can prevent the translocation of the remaining Bcl-2 to the cytoplasm by binding to Bcl-2 in a CHOP-dependent manner, and this effect also contributes to Beclin-1-initiated autophagy. Thus, CHOP is critical for mediating ASPP2-induced autophagic apoptosis by decreasing Bcl-2 expression and maintaining nuclear ASPP2-Bcl-2 complexes. Our results, which define a mechanism whereby ASPP2 overexpression induces autophagic apoptosis, open a new avenue for promoting autophagy in treatments to cure hepatocellular carcinoma.
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: K
authors.initials: K
authors.lastname: Liu
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: M
authors.initials: M
authors.lastname: Hao
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: L
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.affiliation: 1] Beijing You'an Hospital, Capital Medical University, Beijing 100069, China [2] Beijing Institute of Hepatology, Beijing 100069, China.
authors.forename: D
authors.initials: D
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C497249:DDIT3 protein, human; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C090468:TP53BP2 protein, human; D051742:Transcription Factor CHOP