Differential Regulation of Telomerase Reverse Transcriptase Promoter Activation and Protein Degradation by Histone Deacetylase Inhibition

J Cell Physiol. 2016 Jun;231(6):1276-82. doi: 10.1002/jcp.25226. Epub 2015 Nov 16.

Abstract

Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cellular Senescence / drug effects
  • Disease Models, Animal
  • Gene Expression Regulation
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / antagonists & inhibitors
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Hydroxylamines / pharmacology*
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / enzymology
  • Myocytes, Smooth Muscle / pathology
  • Neointima
  • Promoter Regions, Genetic*
  • Proteolysis
  • Quinolines / pharmacology*
  • RNA Interference
  • Rats
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Transcriptional Activation / drug effects*
  • Transfection
  • Vascular Remodeling / drug effects
  • Vascular System Injuries / drug therapy
  • Vascular System Injuries / genetics
  • Vascular System Injuries / metabolism
  • Vascular System Injuries / pathology

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxylamines
  • Quinolines
  • scriptaid
  • Telomerase
  • Tert protein, mouse
  • Hdac1 protein, rat
  • Hdac2 protein, rat
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases
  • histone deacetylase 3