MicroRNA-21 deficiency suppresses prostate cancer progression through downregulation of the IRS1-SREBP-1 signaling pathway

Cancer Lett. 2022 Jan 28;525:46-54. doi: 10.1016/j.canlet.2021.09.041. Epub 2021 Oct 2.

Abstract

Sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor in lipogenesis and lipid metabolism, is critical for disease progression and associated with poor outcomes in prostate cancer (PCa) patients. However, the mechanism of SREBP-1 regulation in PCa remains elusive. Here, we report that SREBP-1 is transcriptionally regulated by microRNA-21 (miR-21) in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of SREBP-1, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) in Pten/Trp53 double-null mouse embryonic fibroblasts (MEFs) and Pten/Trp53 double-null mutant mice. Strikingly, miR-21 loss significantly reduced cell proliferation and suppressed the prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, miR-21 inactivation decreased the levels of SREBP-1, FASN, and ACC in human PCa cells through downregulation of insulin receptor substrate 1 (IRS1)-mediated transcription and induction of cellular senescence. Conversely, miR-21 overexpression increased cell proliferation and migration; as well as the levels of IRS1, SREBP-1, FASN, and ACC in human PCa cells. Our findings reveal that miR-21 promotes PCa progression by activating the IRS1/SREBP-1 axis, and targeting miR-21/SREBP-1 signaling pathway can be a novel strategy for controlling PCa malignancy.

Keywords: ACC; FASN; Fatty acid signaling and mouse models; PTEN; TP53.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetyl-CoA Carboxylase / genetics
  • Animals
  • Cell Proliferation / genetics
  • Disease Progression
  • Fatty Acid Synthase, Type I / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Heterografts
  • Humans
  • Insulin Receptor Substrate Proteins / genetics*
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / genetics*

Substances

  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • MIRN21 microRNA, human
  • MicroRNAs
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • ACACA protein, human
  • Acetyl-CoA Carboxylase