title: ATG4B promotes colorectal cancer growth independent of autophagic flux.
abstract: Autophagy is reported to suppress tumor proliferation, whereas deficiency of autophagy is associated with tumorigenesis. ATG4B is a deubiquitin-like protease that plays dual roles in the core machinery of autophagy; however, little is known about the role of ATG4B on autophagy and proliferation in tumor cells. In this study, we found that ATG4B knockdown induced autophagic flux and reduced CCND1 expression to inhibit G 1/S phase transition of cell cycle in colorectal cancer cell lines, indicating functional dominance of ATG4B on autophagy inhibition and tumor proliferation in cancer cells. Interestingly, based on the genetic and pharmacological ablation of autophagy, the growth arrest induced by silencing ATG4B was independent of autophagic flux. Moreover, dephosphorylation of MTOR was involved in reduced CCND1 expression and G 1/S phase transition in both cells and xenograft tumors with depletion of ATG4B. Furthermore, ATG4B expression was significantly increased in tumor cells of colorectal cancer patients compared with adjacent normal cells. The elevated expression of ATG4B was highly correlated with CCND1 expression, consistently supporting the notion that ATG4B might contribute to MTOR-CCND1 signaling for G 1/S phase transition in colorectal cancer cells. Thus, we report that ATG4B independently plays a role as a positive regulator on tumor proliferation and a negative regulator on autophagy in colorectal cancer cells. These results suggest that ATG4B is a potential biomarker and drug target for cancer therapy.
authors.affiliation: Department of Medical Education and Research; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan; Department of Biotechnology; Fooyin University; Kaohsiung, Taiwan.
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan; Department of Safety, Health and Environmental Engineering; National Kaohsiung First University of Science and Technology; Kaohsiung, Taiwan.
authors.forename: Chung-Man
authors.initials: CM
authors.lastname: Leung
authors.affiliation: Department of Pediatrics; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan; School of Medicine; National Yang-Ming University; Taipei, Taiwan; Department of Nursing; Tajen University; Pingtung, Taiwan.
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan.
authors.forename: Jin-Shiung
authors.initials: JS
authors.lastname: Cheng
authors.affiliation: Department of Pharmacy and Graduate Institute of Pharmaceutical Technology; Tajen University; Pingtung, Taiwan.
authors.forename: Jih-Jung
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Obstetrics Gynecology; Zuoying Branch of Kaohsiung Armed Forces General Hospital; Kaohsiung, Taiwan.
authors.forename: Chung-Jeu
authors.initials: CJ
authors.lastname: Weng
authors.affiliation: Department of Medical Education and Research; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan.
authors.forename: Kuo-Wang
authors.initials: KW
authors.lastname: Tsai
authors.affiliation: Department of Medical Education and Research; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan.
authors.forename: Chien-Jen
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: Department of Medical Education and Research; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan.
authors.forename: Yen-Chen
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Department of Safety, Health and Environmental Engineering; National Kaohsiung First University of Science and Technology; Kaohsiung, Taiwan.
authors.forename: Ping-Chi
authors.initials: PC
authors.lastname: Hsu
authors.affiliation: Department of Medical Education and Research; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan.
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Pan
authors.affiliation: Department of Medical Education and Research; Kaohsiung Veterans General Hospital; Kaohsiung, Taiwan.
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Shu
mesh_terms: D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008819:Mice, Nude; D010766:Phosphorylation; D016196:S Phase; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071183:Autophagy-Related Proteins; C530104:CCND1 protein, human; D019938:Cyclin D1; D058570:TOR Serine-Threonine Kinases; C507524:ATG4B protein, human; D003546:Cysteine Endopeptidases
keywords: ATG4B; CCND1; MTOR; autophagy; colorectal cancer; tumor proliferation