Theranostics 2021; 11(12):5794-5812. doi:10.7150/thno.56604

Research Paper

MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer

Qiji Li1, Min Wang2, Yanqing Hu1, Ensi Zhao1, Jun Li3, Liangliang Ren4, Meng Wang5, Yuandong Xu3, Qian Liang6, Di Zhang6, Yingrong Lai7, Shaoyu Liu1, Xinsheng Peng2, Chengming Zhu6✉, Liping Ye6✉

1. Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
2. Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
3. Department of Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
4. Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
5. Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
6. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
7. Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.

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Citation:
Li Q, Wang M, Hu Y, Zhao E, Li J, Ren L, Wang M, Xu Y, Liang Q, Zhang D, Lai Y, Liu S, Peng X, Zhu C, Ye L. MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer. Theranostics 2021; 11(12):5794-5812. doi:10.7150/thno.56604. Available from https://www.thno.org/v11p5794.htm

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Abstract

Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure.

Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays.

Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa.

Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.

Keywords: Prostate cancer, Castration resistance, Hippo-YAP pathway, RhoA activation, MYBL2.