Pyruvate dehydrogenase phosphatase 1 (PDP1) stimulates HIF activity by supporting histone acetylation under hypoxia.

Abstract

Cancer cells, when exposed to the hypoxic tumour microenvironment, respond by activating hypoxia-inducible factors (HIFs). HIF-1 mediates extensive metabolic re-programming, and expression of HIF-1α, its oxygen-regulated subunit, is associated with poor prognosis in cancer. Here we analyse the role of pyruvate dehydrogenase phosphatase 1 (PDP1) in the regulation of HIF-1 activity. PDP1 is a key hormone-regulated metabolic enzyme that dephosphorylates and activates pyruvate dehydrogenase (PDH), thereby stimulating the conversion of pyruvate into acetyl-CoA. Silencing of PDP1 down-regulated HIF transcriptional activity and the expression of HIF-dependent genes, including that of PDK1, the kinase that phosphorylates and inactivates PDH, opposing the effects of PDP1. Inversely, PDP1 stimulation enhanced HIF activity under hypoxia. Alteration of PDP1 levels or activity did not have an effect on HIF-1α protein levels, nuclear accumulation or interaction with its partners ARNT and NPM1. However, depletion of PDP-1 decreased histone H3 acetylation of HIF-1 target gene promoters and inhibited binding of HIF-1 to the respective hypoxia-response elements (HREs) under hypoxia. Furthermore, the decrease of HIF transcriptional activity upon PDP1 depletion could be reversed by treating the cells with acetate, as an exogenous source of acetyl-CoA, or the histone deacetylase (HDAC) inhibitor trichostatin A. These data suggest that the PDP1/PDH/HIF-1/PDK1 axis is part of a homeostatic loop which, under hypoxia, preserves cellular acetyl-CoA production to a level sufficient to sustain chromatin acetylation and transcription of hypoxia-inducible genes.