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Sox5 contributes to prostate cancer metastasis and is a master regulator of TGF-β-induced epithelial mesenchymal transition through controlling Twist1 expression

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Abstract

Background:

Metastatic castration-resistant prostate cancer (mCRPC) is one of the main contributors to the death of prostate cancer patients. To date, the detailed molecular mechanisms underlying mCRPC are unclear. Given the crucial role of epithelial–mesenchymal transition (EMT) in cancer metastasis, we aimed to analyse the expression and function of Transforming growth factor-beta (TGF-β) signal-associated protein named Sox5 in mCRPC.

Methods:

The protein expression levels were analysed by western blot, immunohistochemistry and immunofluorescence. Luciferase reporter assays and chromatin immunoprecipitation were employed to validate the target of Sox5. The effect of Smad3/Sox5/Twist1 on PCa progression was investigated in vitro and in vivo.

Results:

Here, we found that TGF-β-induced EMT was accompanied by increased Sox5 expression. Interestingly, knockdown of Sox5 expression attenuated EMT induced by TGF-β signalling. Furthermore, we demonstrated that Smad3 could bind to the promoter of Sox5 and regulate its expression. Mechanistically, Sox5 could bind to Twist1 promoter and active Twist1, which initiated EMT. Importantly, knockdown of Sox5 in prostate cancer cells resulted in less of the mesenchymal phenotype and cell migration ability. Furthermore, targeting Sox5 could inhibit prostate cancer progression in a xenograft mouse model. In clinic, patients with high Sox5 expression were more likely to suffer from metastases, and high Sox5 expression also has a lower progression-free survival and cancer specific-survival in clinic database.

Conclusions:

Therefore, we propose a new mechanism in which Smad3/Sox5/Twist1 promotes EMT and contributes to PCa progression.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81302211, 81472682, and 81772756) and Natural Science Foundation of Tianjin (17JCZDJC35300, 15JCZDJC35400, and 15JCYBJC27200). Statement of ethical approval: The study design and procedures were approved by the ethical Committee of Tianjin Medical University (Approval number: KY2017K010).

Author information

Author notes

    • Jieping Hu
    • , Jing Tian
    •  & Shimiao Zhu

    These authors contributed equally to this work.

Affiliations

  1. Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Pingjiang Rd 23#, Hexi District, Tianjin 300211, China

    • Jieping Hu
    • , Jing Tian
    • , Shimiao Zhu
    • , Libin Sun
    • , Jianpeng Yu
    • , Hao Tian
    • , Qian Dong
    • , Qiang Luo
    • , Ning Jiang
    • , Yuanjie Niu
    •  & Zhiqun Shang
  2. Department of Urology, the First Affiliated Hospital of Nanchang University, Jiangxi 330000, China

    • Jieping Hu
  3. Department of Urology, First Affiliated Hospital, Shanxi Medical University, Shanxi 030001, China

    • Libin Sun

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to Yuanjie Niu or Zhiqun Shang.

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