title: CKIP-1 acts as a colonic tumor suppressor by repressing oncogenic Smurf1 synthesis and promoting Smurf1 autodegradation.
abstract: Dysregulation of cellular signaling pathways can lead to colon cancer. However, research on the key signaling effectors or regulators in colon carcinogenesis is limited. Casein kinase-2 interacting protein-1 (CKIP-1; also known as PLEKHO1) is crucial during adult bone formation and is a promising drug target for osteoporosis therapy. In this study, we observed that CKIP-1 was downregulated in human colon cancer tissues and colon cancer cell lines, and this result was correlated with colon cancer progression. CKIP-1 silencing in colon cancers involved promoter methylation. In colon cancer HCT116 and SW480 cells, CKIP-1 overexpression inhibited cell growth and migration. CKIP-1 also suppressed in-vivo tumor formation. Notably, the growth-suppressive role of CKIP-1 was dependent on the downregulation of the cell cycle-regulated oncogene Smad ubiquitylation regulatory factor-1 (Smurf1). During cell cycle progression, phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling increased Smurf1 production by an mTOR-dependent translational control mechanism. Rapamycin, the mTOR inhibitor, significantly reduced Smurf1 protein levels, and Smurf1 was degraded in mitosis. In colon cancer, CKIP-1 controlled Smurf1 expression by suppressing PI3K/Akt/mTOR signaling and enhancing Smurf1 autodegradation, and CKIP-1 downregulation was correlated with Smurf1 upregulation in colon carcinogenesis. These findings provide novel insight into the mechanisms of the candidate tumor suppressor CKIP-1.
authors.affiliation: 1] Department of Molecular Biology, Institute of Basic Medicine, PLA General Hospital, Beijing, China [2] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Nie
authors.affiliation: Department of General Surgery, PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: G
authors.initials: G
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China [2] School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: R
authors.initials: R
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology and Hepatology, PLA General Hospital, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Molecular Biology, Institute of Basic Medicine, PLA General Hospital, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: P
authors.initials: P
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China [2] School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Molecular Biology, Institute of Basic Medicine, PLA General Hospital, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.affiliation: 1] State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China [2] Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D059748:Proteolysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C408877:PLEKHO1 protein, human; D025521:Tumor Suppressor Proteins; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D058570:TOR Serine-Threonine Kinases