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

Oncogene volume 33, pages 3677–3687 (2014)Cite this article

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A Corrigendum to this article was published on 11 February 2016

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.

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Abbreviations

BMP:

bone morphogenetic protein

CKIP-1:

casein kinase-2 interacting protein-1

EGFR:

epidermal growth factor receptor

GSK3:

glycogen synthase kinase-3

mTOR:

mammalian target of rapamycin

PI3K:

phosphatidylinositol-3-kinase

Smurf1:

Smad ubiquitylation regulatory factor-1

TGF-β:

transforming growth factor-β.

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Acknowledgements

The excellent technical assistance of Qian Mei and Zhiqiang Wu is gratefully acknowledged. The study was supported by the National Basic Research Programs (2012CB910702, 2011CB910602 and 2012CB518103) and National Natural Science Foundation Projects (31125010, 31100554, 31270820, 31230061 and 81221004) and Beijing Nova Program (Z121107002512121).

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Author notes

  1. J Nie, L Liu, G Xing and M Zhang: These authors contributed equally to this work.

  2. W Han and L Zhang: WH and LZ contributed equally and share last authorship.

Authors and Affiliations

  1. Department of Molecular Biology, Institute of Basic Medicine, PLA General Hospital, Beijing, China

    J Nie, X Li & W Han

  2. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China

    J Nie, G Xing, M Zhang, R Wei, P Xie, L Li, F He & L Zhang

  3. Department of General Surgery, PLA General Hospital, Beijing, China

    L Liu

  4. School of Life Sciences, Tsinghua University, Beijing, China

    R Wei & F He

  5. Department of Gastroenterology and Hepatology, PLA General Hospital, Beijing, China

    M Guo

  6. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China

    L Zhang

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  1. J Nie
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Correspondence to W Han or L Zhang.

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Nie, J., Liu, L., Xing, G. et al. CKIP-1 acts as a colonic tumor suppressor by repressing oncogenic Smurf1 synthesis and promoting Smurf1 autodegradation. Oncogene 33, 3677–3687 (2014). https://doi.org/10.1038/onc.2013.340

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