CKIP-1 acts as a colonic tumor suppressor by repressing oncogenic Smurf1 synthesis and promoting Smurf1 autodegradation

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.