Decreased extracellular pH induces sustained global histone deacetylation.

  • Major finding: Decreased extracellular pH induces sustained global histone deacetylation.

  • Mechanism: Acetate released by histone deacetylation is coexported with protons to buffer intracellular pH.

  • Impact: An alternate mechanism of HDAC inhibitor activity may involve disruption of pH-buffering capacity.

Global alterations in histone acetylation levels have been observed in both normal and cancer cells and can be prognostic of clinical outcome. However, unlike site-specific acetylation changes that can affect transcription of particular genes, the reason for genome-wide changes has been less clear. Because acetyl-coA molecules required for histone acetylation and acetate anions generated by histone deacetylation are required for many metabolic processes, McBrian and colleagues hypothesized that metabolic or physiologic cues might affect global histone acetylation levels. Systematic testing of the effects of culture medium components on histone acetylation revealed that decreased sodium bicarbonate concentrations resulting in lowered extracellular and intracellular pH led to a rapid, marked reduction in total levels of histone H3 and H4 acetylation at multiple lysine residues. These pH-dependent changes were specific to histone acetylation, as histone methylation was unaffected and required histone deacetylase (HDAC) activity. Chromatin immunoprecipitation sequencing analysis showed that a decrease in extracellular pH led to an extreme redistribution and decreased overall levels of histone H4 lysine 16 acetylation, although these changes were not correlated with changes in gene expression. Export of acetate anions released by histone deacetylation increased as extracellular pH decreased and was dependent on monocarboxylate transporters (MCT), which bidirectionally cotransport acetate with protons. In this manner, continual histone deacetylation can promote proton efflux to buffer against further reduction of intracellular pH. Under conditions of low extracellular pH, HDAC inhibition prevented acetate release and proton efflux and reduced intracellular pH, showing that both HDACs and MCTs are necessary for cellular pH-buffering capacity. In addition to establishing a role for chromatin as an intracellular pH buffer, these findings raise the possibility that HDAC inhibitors may have an alternative mechanism of action as cancer therapeutics involving deregulation of intracellular pH control.

McBrian MA, Behbahan IS, Ferrari R, Su T, Huang TW, Li K, et al. Histone acetylation regulates intracellular pH. Mol Cell 2012 Nov 29 [Epub ahead of print].

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