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p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer

Oncogene volume 36, pages 60–70 (2017)Cite this article

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Abstract

SCFSkp2/Cks1 ubiquitinates Thr187-phosphorylated p27 for degradation. Overexpression of Skp2 coupled with underexpression of p27 are frequent characteristics of cancer cells. When the role of SCFSkp2/Cks1-mediated p27 ubiquitination in cancer was specifically tested by p27 Thr187-to-Ala knockin (p27T187A KI), it was found dispensable for KrasG12D-induced lung tumorigenesis but essential for Rb1-deficient pituitary tumorigenesis. Here we identify pRb and p53 doubly deficient (DKO) prostate tumorigenesis as a context in which p27 ubiquitination by SCFSkp2/Cks1 is required for p27 downregulation. p27 protein accumulated in prostate when p27T187A KI mice underwent DKO prostate tumorigenesis. p27T187A KI or Skp2 knockdown (KD) induced similar degrees of p27 protein accumulation in DKO prostate cells, and Skp2 KD did not further increase p27 protein in DKO prostate cells that contained p27T187A KI (AADKO prostate cells). p27T187A KI activated an E2F1-p73-apoptosis axis in DKO prostate tumorigenesis, slowed disease progression and significantly extended survival. Querying co-occurrence relationships among RB1, TP53, PTEN, NKX3-1 and MYC in TCGA of prostate cancer identified co-inactivation of RB1 and TP53 as the only statistically significant co-occurrences in metastatic castration-resistant prostate cancer (mCRPC). Together, our study identifies Skp2/Cks1 pocket inhibitors as potential therapeutics for mCRPC. Procedures for establishing mCRPC organoid cultures from contemporary patients were recently established. An Skp2/Cks1 pocket inhibitor preferentially collapsed DKO prostate tumor organoids over AADKO organoids, which spontaneously disintegrated over time when DKO prostate tumor organoids grew larger, setting the stage to translate mouse model findings to precision medicine in the clinic on the organoid platform.

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Acknowledgements

This work was supported by NIH grants RO1CA127901and RO1CA131421 (LZ), Albert Einstein Comprehensive Cancer Research Center (5P30CA13330) and Liver Research Center (5P30DK061153) provided core facility support. HZ was a recipient of DOD PCRP Postdoctoral Fellowship (PC121837), and LZ was a Irma T Hirschl Career Scientist Award recipient. We thank Dr James Roberts for providing the p27T187A KI mice.

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Author notes

  1. Z Lu

    Present address: 4Present address: College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China.,

  2. H Fu

    Present address: 5Present address: Department of Biochemistry, Shenyang Medical College, Shenyang, Liaoning 110034, China.,

  3. H Zhao and Z Lu: Co-first authors.

Authors and Affiliations

  1. Departments of Developmental and Molecular Biology, and Ophthalmology and Visual Sciences, and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA

    H Zhao, Z Lu, F Bauzon, H Fu, J Cui & L Zhu

  2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J Locker

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Zhao, H., Lu, Z., Bauzon, F. et al. p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer. Oncogene 36, 60–70 (2017). https://doi.org/10.1038/onc.2016.175

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