Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Mol Cell. 2013 Jan 24;49(2):310-21. doi: 10.1016/j.molcel.2012.10.025. Epub 2012 Nov 29.
Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason why cells regulate these levels has been unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pH(i)). As pH(i) decreases, histones are globally deacetylated by histone deacetylases (HDACs), and the released acetate anions are coexported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pH(i). Conversely, global histone acetylation increases as pH(i) rises, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pH(i), particularly compromising pH(i) maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation throughout the genome. Thus, acetylation of chromatin functions as a rheostat to regulate pH(i) with important implications for mechanism of action and therapeutic use of HDAC inhibitors.
尽管细胞调节这些水平的原因尚不清楚，但正常细胞和癌细胞中的组蛋白乙酰化水平存在差异。在这里，我们证明了组蛋白乙酰化在调节细胞内 pH（pH（i））中的作用。随着 pH（i）的降低，组蛋白被组蛋白去乙酰化酶（HDACs）整体去乙酰化，释放的乙酸盐阴离子通过单羧酸转运蛋白（MCTs）与质子一起被共输出细胞，防止 pH（i）进一步降低。相反，当静止细胞被诱导增殖时，随着 pH（i）的升高，组蛋白的整体乙酰化增加。抑制 HDAC 或 MCT 会减少乙酸盐的输出并降低 pH（i），特别是在酸性环境中会严重影响 pH（i）的维持。在低 pH 下的整体去乙酰化在基因组水平上反映为乙酰化在整个基因组中的丰度降低和广泛重分布。因此，染色质的乙酰化作为变阻器，调节 pH（i），这对 HDAC 抑制剂的作用机制和治疗用途具有重要意义。
