The kinesin KIF20A promotes progression to castration-resistant prostate cancer through autocrine activation of the androgen receptor

Oncogene. 2022 May;41(20):2824-2832. doi: 10.1038/s41388-022-02307-9. Epub 2022 Apr 13.

Abstract

Prostate cancer that recurs following androgen-deprivation therapy is termed castration-resistant, which is incurable and is marked by reactivation of androgen receptor (AR) signaling. KIF20A, a kinesin with unique structural features, is overexpressed in human castration-resistant prostate cancer (CRPC) compared to androgen-dependent PC and benign tissue. KIF20A has well-described roles in mitotic processes, but it has a less characterized function in vesicle fission and trafficking within Golgi-driven secretory pathways. Stable expression of KIF20A in androgen-dependent PC cells promoted progression to CRPC through the activation of AR signaling in vitro and in vivo. KIF20A expression resulted in the secretion of autocrine factors in the conditioned media that activated AR and caused castration-resistant proliferation of naïve androgen-dependent cells. Pharmacologic disruption of vesicle biogenesis blocked KIF20A-driven castration-resistant proliferation of androgen-dependent PC. KIF20A depletion or treatment with the KIF20A-specific inhibitor, paprotrain, reduced CRPC. These data are the first to establish KIF20A as a driver of CRPC progression through AR activation and as a promising therapeutic target against CRPC.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgens / metabolism
  • Cell Line, Tumor
  • Humans
  • Kinesins* / genetics
  • Male
  • Neoplasm Recurrence, Local
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Receptors, Androgen* / genetics
  • Receptors, Androgen* / metabolism

Substances

  • Androgen Antagonists
  • Androgens
  • KIF20A protein, human
  • Receptors, Androgen
  • Kinesins