Histone Deacetylase 7 regulates master transcription factors and modulates mitochondrial function

Reprogramming of the cellular metabolism towards glycolysis (“Warburg effect”) increases mitochondrial membrane potential (ΔΨm) and apoptosis resistance are known hallmarks of cancer. Similarly, pulmonary arterial smooth muscle cells derived from pulmonary arterial hypertensive patients (PAH-PASMCs) have hyperpolarized mitochondria, suppressed glucose oxidation and reduced mitochondria-dependent apoptosis. Signals from suppressed mitochondria may regulate the nuclear trafficking of master transcription factors (e.g. HIF-1α, STAT3, FOXOs) through modulation of their acetylation and/or phosphorylation. We observed that HDAC7 expression is the only commonly upregulated class IIa HDACs in pulmonary vessels and homogenates of PH and lung cancer (LC). In vivo , HDAC7 upregulation is confined majorly to the medial layer of the pulmonary vasculature in PH lungs. Pharmacological inhibition and genetic ablation of HDAC7 leads to mitochondrial depolarization, increased glucose oxidation and induces cell apoptosis. Interestingly, we identified that specific transcription factors already known to play an important role in both PH and LC, such as FOXOs, HIF-1α and STAT3, are regulated by HDAC7. Moreover, HDAC7 influences the phosphorylation of the AMP-activated protein kinase (AMPK), a highly conserved sensor of energy stress, activated in both cancer and PH. Taken together these findings sustain the hypothesis that HDAC7 acts as a regulator of transcription factors and modulates mitochondrial function. It might represent a link to the several molecular abnormalities so far described in both PH and cancer and its targeting may affect the diverse signals associated with the two conditions.