Key result
HDAC inhibitors or HDAC3 depletion trigger reversible QT prolongation in mice by downregulating potassium channels.
Why the study?
HDAC inhibitors cause cardiac side effects such as QT interval prolongation, but the underlying mechanisms remain unclear.
Does disruption of cardiac HDAC3 or treatment with HDAC inhibitors cause QT prolongation and alter potassium channel gene expression in mice?
Does disruption of cardiac HDAC3 or treatment with HDAC inhibitors cause QT prolongation and alter potassium channel gene expression in mice?
Disruption of HDAC3 enzymatic activity causes QT prolongation and alters potassium channel gene expression, providing a mechanistic basis for HDAC inhibitor-associated cardiotoxicity.
HDAC3 loss may underlie HDAC inhibitor QT effects in mice; hypothesis-generating for human cardiotoxicity mechanisms.
Histone deacetylase (HDAC) inhibitors are approved for cancer treatment and are being investigated for a wide range of other diseases. Despite their therapeutic promise, clinical studies have reported cardiac side effects, particularly electrocardiogram (EKG) abnormalities, with QT interval prolongation being one of the most consistently reported findings. The mechanisms underlying these cardiac effects remain unclear. In this study, we investigated the role of HDAC3 in cardiac electrophysiology. We found that postnatal depletion of cardiac HDAC3 in mice caused QT interval prolongation, recapitulating the EKG abnormalities reported with HDAC inhibitor use. Adult-onset inducible depletion of cardiac HDAC3 induced additional EKG abnormalities, including T-wave flattening, inversion, and biphasic T waves, which are also observed clinically. Loss of HDAC3 deacetylase activity, without affecting HDAC3 protein levels, was sufficient to induce QT prolongation. Disruption of HDAC3 function altered the expression of ion channel genes, including the downregulation of potassium channel genes such as Kcnh2, Kcne1, and Kcnip2. Moreover, a single dose of HDAC inhibitors, romidepsin or mocetinostat, caused reversible QT prolongation in mice. Consistent with these findings, HDAC inhibitor treatment altered the expression of potassium channel genes, with a predominant downregulation of multiple Kcn family members, including Kcnq1, Kcnh2, and Kcnip2. These findings establish HDAC3 enzymatic activity as a key regulator of cardiac repolarization and provide mechanistic insight into HDAC inhibitor-associated cardiotoxicity.
No takes yet. Share an insight, caveat, or question.
Lu et al. (2026) studied HDAC inhibitor-induced QT prolongation. HDAC3 depletion or HDAC inhibitors (romidepsin or mocetinostat) was evaluated on QT interval prolongation and EKG abnormalities. Depletion of cardiac HDAC3 or treatment with HDAC inhibitors in mice caused reversible QT interval prolongation and downregulated potassium channel genes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: