A regulative epigenetic circuit supervised by HDAC7 represses IGFBP6 and IGFBP7 expression to sustain mammary stemness

Epigenomics. 2021 May;13(9):683-698. doi: 10.2217/epi-2020-0347. Epub 2021 Apr 21.

Abstract

Background: In the breast, the pleiotropic epigenetic regulator HDAC7 can influence stemness. Materials & Methods: The authors used MCF10 cells knocked-out for HDAC7 to explore the contribution of HDAC7 to IGF1 signaling. Results: HDAC7 buffers H3K27ac levels at the IGFBP6 and IGFBP7 genomic loci and influences their expression. In this manner, HDAC7 can tune IGF1 signaling to sustain stemness. In HDAC7 knocked-out cells, RXRA promotes the upregulation of IGFBP6/7 mRNAs. By contrast, HDAC7 increases FABP5 expression, possibly through repression of miR-218. High levels of FABP5 can reduce the delivery of all-trans-retinoic acid to RXRA. Accordingly, the silencing of FABP5 increases IGFBP6 and IGFBP7 expression and reduces mammosphere generation. Conclusion: The authors propose that HDAC7 controls the uptake of all-trans-retinoic acid, thus influencing RXRA activity and IGF1 signaling.

Keywords: CRABP2; ChIP-seq; FABP5; HDAC7; IGF1; MEF2; breast; miR-218; retinoids; stemness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Epigenesis, Genetic
  • Fatty Acid-Binding Proteins / genetics
  • Histone Deacetylases / genetics*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 6 / genetics*
  • Insulin-Like Growth Factor Binding Proteins / genetics*
  • Insulin-Like Growth Factor I / genetics
  • Mammary Glands, Human / cytology
  • Retinoid X Receptor alpha / genetics

Substances

  • FABP5 protein, human
  • Fatty Acid-Binding Proteins
  • IGF1 protein, human
  • Insulin-Like Growth Factor Binding Protein 6
  • Insulin-Like Growth Factor Binding Proteins
  • RXRA protein, human
  • Retinoid X Receptor alpha
  • insulin-like growth factor binding protein-related protein 1
  • Insulin-Like Growth Factor I
  • HDAC7 protein, human
  • Histone Deacetylases