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p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance

Oncogene volume 34, pages 3568–3581 (2015)Cite this article

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Abstract

The DNA damage response (DDR) helps to maintain genome integrity, suppress tumorigenesis and mediate the radiotherapeutic and chemotherapeutic effects on cancer. Here we report that p57Kip2, a cyclin-dependent kinase (CDK) inhibitor implicated in the development of tumor-prone Beckwith–Wiedemann syndrome, is an effector molecule of the DNA-damage response. Genotoxic stress induces p57Kip2 expression via the bone morphogenetic protein-Smad1 and Atm-p38MAPK-Atf2 pathways in p53-proficient or -deficient cells and requires the Smad1-Atf2 complex that facilitates their recruitment to the p57Kip2 promoter. Elevated p57Kip2 induces G1/S phase cell cycle arrest but inhibits cell death in response to DNA damage and acts in parallel with p53 to suppress cell transformation and tumor formation. p57Kip2 is also upregulated in stage I and II clinical rectal tumor samples, likely due to genome instability of precancerous and/or early cancer cells. Targeting p57Kip2 in primary rectal cancer cells and tumor models resulted in increased sensitivity to doxorubicin, suggesting that p57Kip2 has a role in chemoresistance, which is consistent with its pro-survival function. These findings place p57Kip2 in DDR and uncover molecular mechanisms by which p57Kip2 suppresses tumorigenesis and causes chemoresistance.

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Acknowledgements

We thank Lina Gao, IH In, C Deyu, GC Hong, L Soh, J Lin and T Cheng for technical assistance and Boehringer Ingelheim, Novartis, Dr Michael D. Schneider, Dr Ye-Guang Chen, Dr Yibin Wang, Dr Nelson J Dusetti, Dr Olivier Delattre, Dr Philipp Kaldis and Dr Michael Kastan for providing constructs, reagents and mice. The work was supported by grants from the Ministry of Science and Technology of China (The National Key Scientific Program (2012CB966901 to BL) and the National Natural Science Foundation of China (81130039, 31071229 and 81121001).

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  1. H Jia and Q Cong: These authors contributed equally to this work.

Authors and Affiliations

  1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

    H Jia, Q Cong, H Liu, X Xia, X Zhang, J Lin & B Li

  2. The Institute of Molecular and Cell Biology, Singapore, Singapore

    J F L Chua

  3. South Texas Veterans Health Care System and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    S L Habib

  4. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    J Ao

  5. Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China

    Q Zuo & C Fu

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Jia, H., Cong, Q., Chua, J. et al. p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance. Oncogene 34, 3568–3581 (2015). https://doi.org/10.1038/onc.2014.287

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