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The essential role of WD repeat domain 77 in prostate tumor initiation induced by Pten loss

Oncogene volume 37, pages 4151–4163 (2018)Cite this article

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Abstract

Prostate cancer is the most commonly diagnosed malignancy among men, but few genetic factors that drive prostate cancer initiation have been identified. The WD repeat domain 77 (Wdr77) protein is essential for cellular proliferation when localizes in the cytoplasm of epithelial cells at the early stage of prostate development. In the adult prostate, it is transported into the nucleus and functions as a co-regulator of the androgen receptor to promote cellular differentiation and prostate function. This developmental process is reversed during prostate tumorigenesis, i.e., Wdr77 is translocated from the nucleus into the cytoplasm to drive proliferation of prostate cancer cells. In this study, we used in vivo genetic studies to further investigate the role of Wdr77 in prostate tumorigenesis. We found that prostate-specific deletion of Wdr77 abolished prostate tumor initiation induced by loss of the tumor suppressor Pten. Mechanistically, Wdr77 ablation inhibited E2F3 activation and enhanced TGFβ signaling, leading to attenuated cellular proliferation induced by loss of Pten. These findings establish a critical role of Wdr77 for prostate tumor initiation.

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Acknowledgements

We thank Ms. Shen Gao for animal work and technique support. DOB is supported by NIH NIGMS-RISE R25GM06414 and ZW is supported by W81XWH-12-1-0453 PC111461, NIMHD RCMI 5G12MD007590, and NIMHD 5P20MD002285. The funding agencies had no role in study design, data collection or analysis, decision to publish or manuscript preparation.

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  1. Department of Biological Sciences, The Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, 30314, USA

    Deon O’Bryant & Zhengxin Wang

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Correspondence to Zhengxin Wang.

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O’Bryant, D., Wang, Z. The essential role of WD repeat domain 77 in prostate tumor initiation induced by Pten loss. Oncogene 37, 4151–4163 (2018). https://doi.org/10.1038/s41388-018-0254-8

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