title: 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.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Road, Shanghai 201318, People's Republic of China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Liang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Guoke
authors.initials: G
authors.lastname: Liu
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Rongjie
authors.initials: R
authors.lastname: Jia
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.|General Hospital of Lanzhou Military Command, 333 South Binhe Road, Lanzhou 730050, People's Republic of China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Fan
authors.affiliation: Changhai Hospital, The Second Military Medical University, 168 Changhai Road, Shanghai 200433, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jing
authors.affiliation: Changhai Hospital, The Second Military Medical University, 168 Changhai Road, Shanghai 200433, People's Republic of China.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Huajing
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Cancer Center Key Lab, PLA General Hospital, 28 Fuxing Road, Beijing 100853, People's Republic of China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C090468:TP53BP2 protein, human; D051996:Transcription Factor RelA