Histone deacetylase inhibitors modulate KATP subunit transcription in HL-1 cardiomyocytes through effects on cholesterol homeostasis

Frontiers in Pharmacology

William C Claycomb¹  Tristan M Sissung²  Susan E. Bates²  Mark C Haigney³  Thomas P Flagg³  Naheed eFatima³  Gauthaman eSukumar³  Devin C Cohen³  Clifton Lee Dalgard³  James F Schooley³  Rachel T Cox³ 

[1] LSU Health Sciences Center;National Institutes of Health;Uniformed Services University of the Health Sciences;

关键词: Cholesterol;    epigenetics;    Romidepsin;    ABCC9;    ABCC8;    SREBP;   

DOI  :  10.3389/fphar.2015.00168

来源: DOAJ

【 摘 要 】

Histone deacetylase inhibitors (HDIs) are under investigation for the treatment of a number of human health problems. HDIs have proven therapeutic value in refractory cases of cutaneous T-cell lymphoma,. Electrocardiographic ST segment morphological changes associated with HDIs were observed during development. Because ST segment morphology is typically linked to changes in ATP sensitive potassium (KATP) channel activity, we tested the hypothesis that HDIs affect cardiac KATP channel subunit expression. Two different HDIs, romidepsin and trichostatin A, caused ~20 fold increase in SUR2 (Abcc9) subunit mRNA expression in HL-1 cardiomyocytes. The effect was specific for the SUR2 subunit as neither compound causes a marked change in SUR1 (Abcc8) expression. Moreover, the effect was cell specific as neither HDI markedly altered KATP subunit expression in MIN6 pancreatic β-cells. We observe significant enrichment of the H3K9Ac histone mark specifically at the SUR2 promoter consistent with the conclusion that chromatin remodeling at this locus plays a role in increasing SUR2 gene expression. Unexpectedly, however, we also discovered that HDI-dependent depletion of cellular cholesterol is required for the observed effects on SUR2 expression. Taken together, the data in the present study demonstrate that KATP subunit expression can be epigenetically regulated in cardiomyocytes, defines a role for cholesterol homeostasis in mediating epigenetic regulation and suggests a potential molecular basis for the cardiac effects of the HDIs.

【 授权许可】

Unknown