Decline of p300 contributes to cell senescence and growth inhibition of hUC-MSCs through p53/p21 signaling pathway

Biochem Biophys Res Commun. 2019 Jul 12;515(1):24-30. doi: 10.1016/j.bbrc.2019.05.061. Epub 2019 May 20.

Abstract

Human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in vitro expansion for long term may undergo epigenetic and genetic alterations that subsequently induce cellular senescence and associated growth inhibition. Increasing evidence implicated that aberrant histone acetylation modulates gene expression responsible for MSCs aging. Whether the dysregulation of p300 and its KAT activity is involved in the aging process of MSCs was still unexplored. In this study, we found a significant decrease of p300 but elevated p53/p21 levels in senescent hUC-MSCs at late-passage. Then we used two different approaches: (i) downregulation of p300 by siRNA and (ii) inhibition of the acetyltransferase(KAT) activity by C646 to determine the role of p300 in regulating MSCs senescence. We showed that inhibition of p300 induce premature senescence and decrease proliferation potential in hUC-MSCs. Moreover, upregulations of p53 and p21 expressions were confirmed in p300 knockdown and C646-treated hUC-MSCs. Taken together, these results suggest that p300 plays an important role in aging process of MSCs associated with activation of p53/p21 signaling pathway.

Keywords: C646 inhibitor; Cellular senescence; hUC-MSCs; p300; p53/p21 signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoates / pharmacology
  • Cell Culture Techniques
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cellular Senescence* / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • E1A-Associated p300 Protein / antagonists & inhibitors
  • E1A-Associated p300 Protein / deficiency*
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Nitrobenzenes
  • Pyrazoles / pharmacology
  • Pyrazolones
  • Signal Transduction* / drug effects
  • Tumor Suppressor Protein p53 / metabolism*
  • Umbilical Cord / cytology*

Substances

  • 4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid
  • Benzoates
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Nitrobenzenes
  • Pyrazoles
  • Pyrazolones
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • E1A-Associated p300 Protein
  • EP300 protein, human