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Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer

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Abstract

Thalidomide is experimentally used to treat various human cancers; however, clinical responses to thalidomide are sporadic. Here we demonstrate that CUL4A plays an oncogenic role in prostate cancer development and prostate cancer cells with higher level of CUL4A are particularly sensitive to thalidomide treatment. We show that CUL4A is frequently overexpressed in human primary prostate cancer and cell lines. Notably, subjects with tumors that highly expressed CUL4A had poor overall survival. CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo, whereas CUL4A overexpression transformed human normal prostate epithelial cells and promoted invasion, which was attenuated by the extracellular signal-regulated kinase (ERK) inhibitor. We further show that the sensitivity to thalidomide is positively correlated with CUL4A expression in a panel of prostate cell lines. Ectopic CUL4A expression greatly enhanced sensitivity to thalidomide, while its downregulation conferred resistance to this drug. Mechanistically, thalidomide decreased CUL4A in a time- and dose-dependent manner, consequently leading to inaction of ERK pathway. Finally, we show that cereblon level is correlated with CUL4A expression and downregulated in thalidomide-resistant prostate cancer cell. Our results offer the first evidence that CUL4A is a potential therapeutic target for prostate cancer and may serve as a biomarker for assessing prognosis of human prostate cancer and response to thalidomide treatment.

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Acknowledgments

This work was supported by funding from the National Basic Research Program of China (no. 2012CB518300, YHS), the National Natural Science Foundation of China (no. 81101946, SCR), Key Basic Research Programme of Shanghai (no. 09DJ1400400, YHS), and the National Institutes of Health, National Cancer Institute grant R01 CA116481, Office of Biological & Environmental Research, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231, and Laboratory Directed Research & Development Program (LDRD, JHM).

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The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, No. 168, Changhai Rd, Yangpu District, Shanghai, 200433, China

    Shancheng Ren, Chuanliang Xu, Zilian Cui, Yongwei Yu, Weidong Xu, Fubo Wang, Ji Lu, Min Wei, Xin Lu, Xu Gao & Yinghao Sun

  2. Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA, 94143, USA

    You Liang

  3. Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA, 94720, USA

    Jian-Hua Mao

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  1. Shancheng Ren
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Correspondence to Jian-Hua Mao or Yinghao Sun.

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These authors Shancheng Ren, Chuanliang Xu, and Zilian Cui contributed equally to this work.

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Ren, S., Xu, C., Cui, Z. et al. Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer. J Mol Med 90, 1121–1132 (2012). https://doi.org/10.1007/s00109-012-0885-0

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