title: The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades.
abstract: Ataxia-telangiectasia mutated (ATM) protein kinase is a major guardian of genomic stability, and its well-established function in cancer is tumor suppression. Here, we report an oncogenic role of ATM. Using two isogenic sets of human colon cancer cell lines that differed only in their ATM status, we demonstrated that ATM deficiency significantly inhibits cancer cell proliferation, migration, and invasion. The tumor-suppressive function of ATM depletion is not modulated by the compensatory activation of ATR, but it is associated with B56γ2-mediated Chk1/p53/CD44 signaling pathways. Under normal growth conditions, the depletion of ATM prevents B56γ2 ubiquitination and degradation, which activates PP2A-mediated Chk1/p53/p21 signaling pathways, leading to senescence and cell cycle arrest. CD44 was validated as a novel ATM target based on its ability to rescue cell migration and invasion defects in ATM-depleted cells. The activation of p53 induced by ATM depletion suppresses CD44 transcription, thus resulting in epithelial-mesenchymal transition (EMT) and cell migration suppression. Our study suggests that ATM has tumorigenic potential in post-formed colon neoplasia, and it supports ATM as an appealing target for improving cancer therapy.
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Tang
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Chaodong
authors.initials: C
authors.lastname: Ding
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Liang
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Tianke
authors.initials: T
authors.lastname: Chen
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Dai
authors.affiliation: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Li
authors.affiliation: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Hu
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Liting
authors.initials: L
authors.lastname: Lu
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Wanqin
authors.initials: W
authors.lastname: Liao
authors.affiliation: School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: xinchenglu@yahoo.com.
authors.forename: Xincheng
authors.initials: X
authors.lastname: Lu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D000071877:Checkpoint Kinase 1 / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C112123:B56 protein, human; D001798:Blood Proteins; D018960:Hyaluronan Receptors; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1
keywords: ATM; B56γ2; CD44; Colon cancer; Tumorigenic potential