title: ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2.
abstract: Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene BECN1 (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Yuan
authors: Y
authors: Peng
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Hongming
authors: H
authors: Miao
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Shuang
authors: S
authors: Wu
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Weiwen
authors: W
authors: Yang
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Yue
authors: Y
authors: Zhang
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Ganfeng
authors: G
authors: Xie
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Xiong
authors: X
authors: Xie
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Jianjun
authors: J
authors: Li
authors: b Institute of Combined Injury, State Key Labortory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, The Third Military Medical University , Chongqing , China.
authors: Chunmeng
authors: C
authors: Shi
authors: c Institute of Immunology, The Third Military Medical University , Chongqing , China.
authors: Lilin
authors: L
authors: Ye
authors: d Biomedical Analysis Center, Third Military Medical University , Chongqing , China.
authors: Wei
authors: W
authors: Sun
authors: d Biomedical Analysis Center, Third Military Medical University , Chongqing , China.
authors: Liting
authors: L
authors: Wang
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Houjie
authors: H
authors: Liang
authors: a Department of Oncology and Southwest Cancer Center , Southwest Hospital, The Third Military Medical University , Chongqing , China.
authors: Juanjuan
authors: J
authors: Ou
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1 / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007422:Intestines / Q000473:pathology; D008049:Lipase / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011485:Protein Binding; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000071186:Beclin-1; D053148:Caspase 3; D008049:Lipase; C439972:ABHD5 protein, human; C492986:Abhd5 protein, mouse; C494794:PNPLA2 protein, human; D000217:Acyltransferases
keywords: ABHD5; autophagy; colorectal cancer; genome instability; tumorigenesis