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

Theranostics. 2021 Mar 31;11(12):5794-5812. doi: 10.7150/thno.56604. eCollection 2021.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology
  • Castration / methods
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology
  • Hippo Signaling Pathway
  • Humans
  • Male
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • PC-3 Cells
  • Prognosis
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology*
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Mas
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Up-Regulation / drug effects


  • Androgen Antagonists
  • Cell Cycle Proteins
  • MAS1 protein, human
  • MYBL2 protein, human
  • Proto-Oncogene Mas
  • Receptors, Androgen
  • Trans-Activators
  • Transcription Factors
  • YY1AP1 protein, human
  • Protein Serine-Threonine Kinases