Differential Regulation of Telomerase Reverse Transcriptase Promoter Activation and Protein Degradation by Histone Deacetylase Inhibition.
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.
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky.|Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky.|Department of Endocrinology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Hua
H
Qing
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky.
Jun
J
Aono
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky.
Hannes M
HM
Findeisen
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky.
Karrie L
KL
Jones
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky.
Elizabeth B
EB
Heywood
Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky.|Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
Dennis
D
Bruemmer
D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006898:Hydroxylamines / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058426:Neointima; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects; D057772:Vascular System Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000099186:Histone Deacetylase 3
D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006898:Hydroxylamines; D011804:Quinolines; D019098:Telomerase; D000099186:Histone Deacetylase 3; C410733:scriptaid; C509187:Tert protein, mouse; C515890:Hdac1 protein, rat; C533426:Hdac2 protein, rat