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SPOP regulates prostate epithelial cell proliferation and promotes ubiquitination and turnover of c-MYC oncoprotein

Oncogene volume 36, pages 4767–4777 (2017)Cite this article

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Abstract

The E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) is frequently dysregulated in prostate adenocarcinoma (PC), via either somatic mutations or mRNA downregulation, suggesting an important tumour suppressor function. To examine its physiologic role in the prostate epithelium in vivo, we generated mice with prostate-specific biallelic ablation of Spop. These mice exhibited increased prostate mass, prostate epithelial cell proliferation, and expression of c-MYC protein compared to littermate controls, and eventually developed prostatic intraepithelial neoplasia (PIN). We found that SPOPWT can physically interact with c-MYC protein and, upon exogenous expression in vitro, can promote c-MYC ubiquitination and degradation. This effect was attenuated in PC cells by introducing PC-associated SPOP mutants or upon knockdown of SPOP via short-hairpin-RNA, suggesting that SPOP inactivation directly increases c-MYC protein levels. Gene Set Enrichment Analysis revealed enrichment of Myc-induced genes in transcriptomic signatures associated with SPOPMT. Likewise, we observed strong inverse correlation between c-MYC activity and SPOP mRNA levels in two independent PC patient cohorts. The core SPOPMT;MYCHigh transcriptomic response, defined by the overlap between the SPOPMT and c-MYC transcriptomic programmes, was also associated with inferior clinical outcome in human PCs. Finally, the organoid-forming capacity of Spop-null murine prostate cells was more sensitive to c-MYC inhibition than that of Spop-WT cells, suggesting that c-MYC upregulation functionally contributes to the proliferative phenotype of Spop knock-out prostates. Taken together, our data highlight SPOP as an important regulator of luminal epithelial cell proliferation and c-MYC expression in prostate physiology, identify c-MYC as a novel bona fide SPOP substrate, and help explain the frequent inactivation of SPOP in human PC. We propose SPOPMT-induced stabilization of c-MYC protein as a novel mechanism that can increase total c-MYC levels in PC cells, in addition to amplification of c-MYC locus.

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Acknowledgements

The authors acknowledge the joint participation by Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine. This work was also supported by the American Cancer Society RSG-14-218-01-TBG (to NM), the Prostate Cancer Foundation (to BWO and NM); the Conquer Cancer Foundation of the American Society of Clinical Oncology Young Investigator and Career Development Awards (both to NM) and a Developmental Project from SPORE P50CA58183 (NM); the Pilot/Feasibility Program of the Diabetes and Endocrinology Research Center (P30-DK079638) at Baylor College of Medicine (NM), an Alkek Foundation for Molecular Discovery Pilot grant (CC), CPRIT awards RP170295 and RP170005 (CC); NIH R01CA190378 (LX); NIH 5T32CA174647-03 (SK); and NICHD 8818 and Department of Defense Breast Cancer Research Program Innovator Award (BWO). NM is a Dan L Duncan Scholar, a Caroline Wiess Law Scholar and member of the Center for Drug Discovery at Baylor College of Medicine. The authors also acknowledge the assistance of the BCM Genetically Engineered Mouse and Human Tissue Acquisition and Pathology Core, Human Tissue Acquisition and Pathology Core, Integrated Microscopy Core funded via the NIH (DK56338, and CA125123), CPRIT (RP150578), and John S Dunn Gulf Coast Consortium for Chemical Genomics and the Dan L Duncan Cancer Center (supported by the NCI Cancer Center Support Grant P30CA125123).

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Author notes

  1. C Geng, S Kaochar, M Li and K Rajapakshe: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    C Geng, S Kaochar, M Li, W Fiskus, C Foley, B Dong, S S Shah, M Bolaki & N Mitsiades

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    C Geng, S Kaochar, M Li, K Rajapakshe, W Fiskus, J Dong, C Foley, B Dong, L Zhang, O-J Kwon, S S Shah, M Bolaki, L Xin, B W O'Malley, C Coarfa & N Mitsiades

  3. Dan L Duncan Cancer Center, Houston, TX, USA

    L Xin, M Ittmann, C Coarfa & N Mitsiades

  4. Department of Pathology and Immunology and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    M Ittmann

  5. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA

    N Mitsiades

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  1. C Geng
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Geng, C., Kaochar, S., Li, M. et al. SPOP regulates prostate epithelial cell proliferation and promotes ubiquitination and turnover of c-MYC oncoprotein. Oncogene 36, 4767–4777 (2017). https://doi.org/10.1038/onc.2017.80

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