Cell Death Discovery (May 2021)

Reduced O-GlcNAcylation of SNAP-23 promotes cisplatin resistance by inducing exosome secretion in ovarian cancer

  • Luomeng Qian,
  • Xiaoshan Yang,
  • Shaohui Li,
  • Hang Zhao,
  • Yunge Gao,
  • Shuhui Zhao,
  • Xiaohui Lv,
  • Xiyuan Zhang,
  • Lingxia Li,
  • Lianghao Zhai,
  • Fuxing Zhou,
  • Biliang Chen

DOI
https://doi.org/10.1038/s41420-021-00489-x
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 11

Abstract

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Abstract Exosomes have been associated with chemoresistance in various cancers, but such a role in ovarian cancer is not yet clear. Here, using in vitro cell-based and in vivo mouse model experiments, we show that downregulation of O-GlcNAcylation, a key post-translational protein modification, promotes exosome secretion. This increases exosome-mediated efflux of cisplatin from cancer cells resulting in chemoresistance. Mechanistically, our data indicate that downregulation of O-GlcNAclation transferase (OGT) reduces O-GlcNAclation of SNAP-23. Notably, O-GlcNAcylation of SNAP-23 is vital for regulating exosome release in ovarian cancer cells. Reduced O-GlcNAclation of SNAP-23 subsequently promotes the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex consisting of SNAP-23, VAMP8, and Stx4 proteins. This enhances exosome release causing chemoresistance by increasing the efflux of intracellular cisplatin.