Dynamics of Histone Acetylation in Cancer Cell Physiology

描述（由申请人提供）：我们实验室发现，整体组蛋白乙酰化水平较低的癌症组织显示出肿瘤复发率或癌症相关死亡率显著增加，这一发现已被多个其他实验室独立验证。然而，在正常生物学中，组蛋白乙酰化的全局变化的功能以及它如何可能导致癌症表型一直是完全未知的。我们提供的证据表明，全局组蛋白乙酰化和去乙酰化与醋酸盐和质子在细胞内外的共运输相耦合，有效地使染色质成为细胞内质子负荷的调节剂，从而调节细胞内pH （pHi）。在酸性条件下，

DESCRIPTION (provided by applicant): Our laboratory has discovered that cancer tissues with lower global levels of histone acetylation display significantly increased rate of tumor recurrence or cancer-related mortality, findings that have been validated independently by multiple other laboratories. However, the function of global changes in histone acetylation in normal biology and how it might contribute to the cancer phenotype have been completely unknown. We present evidence that global histone acetylation and deacetylation is coupled to the co-transport of acetate and protons in and out of the cell, effectively making chromatin a regulator of intracellular proton load, and hence, of intracellular pH (pHi). In acidic conditions, histones are globally deacetylated and the resulting acetate molecules are co-transported with protons out of the cell through the monocarboxylate transporters (MCTs), thereby decreasing the intracellular proton load. At alkaline pH, histones are globally acetylated, serving to store acetate molecules and resisting further increases in pHi. Deacetylation of histones at low pH requires continuous histone deacetylase (HDAC) activity and is not due to compromised HAT activity. Inhibition of HDACs or MCTs to decrease acetate availability or export, respectively, lowers pHi and particularly compromises pHi maintenance in acidic microenvironments. Thus histone acetylation functions as a rheostat to regulate pHi. Our data suggest a novel mechanism of action for HDAC inhibitors and raise the possibility that cancer tissues displaying low levels o histone acetylation may be secreting acetate and protons to maintain an alkaline pHi relative to the extracellular environment-a hallmark of rapidly dividing cells. In this application, we aim to determine how global changes in histone acetylation in response to pH map to specific regions of the genome and the consequences for gene expression. We will determine the mechanism of pH- induced histone deacetylation and identify the main MCTs that transport the acetate molecules that are released from chromatin by HDACs. We will also determine how global changes in histone acetylation in response to pH affect the tumorigenic properties of cancer cells. Finally, we will relate the expression of MCTs, localization of HDACs and global histone acetylation levels in fully-annotated primary cancer tissues to determine the clinical relevance of our findings. Our work will add a novel dimension to the functions chromatin and histone acetylation serve for the cell.