KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation

Cell Death Dis. 2024 Nov 6;15(11):796. doi: 10.1038/s41419-024-07142-2.

Abstract

Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma after endocrine treatment failure and implies lethality and limited therapeutic options. Deciphering the molecular mechanisms underlying transdifferentiation from adenocarcinoma to NEPC may provide valuable therapeutic strategies. We performed a pan-cancer differential mRNA abundance analysis and identified that Kinesin-like protein (KIF1A) was highly expressed in NEPC. KIF1A knockdown impaired neuroendocrine(NE) features, including NE marker gene expression, stemness, and epithelial-mesenchymal transition (EMT), whereas KIF1A overexpression promoted these processes. Targeting KIF1A inhibited the growth of NE differentiated prostate cancer (PCa) cells in vitro and in vivo. Mechanistically, KIF1A bound with O-linked N-acetylglucosamine transferase (OGT) and regulated its protein expression and activity. Nuclear accumulation of OGT induced by KIF1A overexpression promoted intranuclear O-GlcNAcylation of β-catenin and OCT4 in nucleus. More importantly, our data revealed that OGT was critical for KIF1A induced NE differentiation and aggressive tumor growth. An OGT inhibitor, OSMI-1, can significantly inhibited NE differentiated PCa cell proliferation in vitro and tumor growth in vivo. Our findings showed that KIF1A promotes NE differentiation to NEPC by regulating the OGT-mediated O-GlcNAcylation. Targeting O-GlcNAcylation may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kinesins* / genetics
  • Kinesins* / metabolism
  • Male
  • Mice
  • Mice, Nude
  • N-Acetylglucosaminyltransferases* / genetics
  • N-Acetylglucosaminyltransferases* / metabolism
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • beta Catenin / metabolism

Substances

  • Kinesins
  • N-Acetylglucosaminyltransferases
  • OGT protein, human
  • KIF1A protein, human
  • beta Catenin
  • Octamer Transcription Factor-3