AUTHOR=Fatima Naheed , Cohen Devin C., Sukumar Gauthaman , Sissung Tristan M., Schooley James F., Haigney Mark C., Claycomb William C., Cox Rachel T., Dalgard Clifton L., Bates Susan E., Flagg Thomas P.

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

JOURNAL=Frontiers in Pharmacology

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2015.00168

DOI=10.3389/fphar.2015.00168

ISSN=1663-9812

ABSTRACT=<p>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 (K<sub>ATP</sub>) channel activity, we tested the hypothesis that HDIs affect cardiac K<sub>ATP</sub> channel subunit expression. Two different HDIs, romidepsin and trichostatin A, caused ~20-fold increase in SUR2 (<italic>Abcc9</italic>) subunit mRNA expression in HL-1 cardiomyocytes. The effect was specific for the SUR2 subunit as neither compound causes a marked change in SUR1 (<italic>Abcc8</italic>) expression. Moreover, the effect was cell specific as neither HDI markedly altered K<sub>ATP</sub> 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 K<sub>ATP</sub> 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.</p>