Dynamics of Global Histone Acetylation in Regulating Intracellular pH

描述（由申请人提供）：我们的小组首次描述了癌症中全局组蛋白乙酰化的预后价值，此后已由多个其他实验室独立验证。这些报告已经发现，在癌组织中，较低的组蛋白乙酰化整体水平与癌症相关的死亡率和发病率显著相关。然而，组蛋白乙酰化的整体变化的功能和调控及其与癌症生物学的相关性一直是完全未知的。最近，我们的小组已经揭示了染色质和全局组蛋白乙酰化作为细胞内质子负荷的调节剂的新作用。我们已经表明，全球组蛋白脱乙酰化耦合到乙酸根离子和质子通过单羧酸转运蛋白（MCT）的细胞外的共转运，允许在酸性条件下调节细胞内pH。相反，组蛋白在碱性pH下被整体乙酰化，以通过螯合乙酸根离子与可用的细胞内质子共转运出细胞来对抗细胞内pH的增加。组蛋白在低pH下的整体脱乙酰化需要连续的组蛋白脱乙酰酶（HDAC）活性，因为HDAC的药理学抑制损害酸性微环境中的pHi维持。该提案旨在确定组蛋白乙酰化变化的精确全基因组分布，以响应细胞内pH值的变化以及对基因表达和癌细胞行为的影响。我们将试图阐明pH诱导的组蛋白去乙酰化的机制，并确定参与调节这一过程的主要HDAC。到目前为止，我们的数据表明，这种新的功能的全局组蛋白乙酰化在癌症组织中的含义。我们推测，癌组织显示低组蛋白乙酰化水平，可能是利用这种机制，以保持一个相对碱性pHi，尽管酸性细胞外环境-一个众所周知的标志，快速分裂的细胞。这项研究的结果将揭示一个新的层面的染色质生物学和组蛋白乙酰化整合控制基因表达与细胞生理学。此外，我们的工作将为HDAC抑制剂（HDACi）在临床中的更有效使用提供新的见解，并有可能揭示HDACi在各种类型癌症中的先天性和获得性抗性机制。

DESCRIPTION (provided by applicant): The prognostic value of global histone acetylation in cancer was first described by our group and has been since validated independently by multiple other laboratories. These reports have discovered that in cancer tissue, a lower global level of histone acetylation is significantly associated with cancer-related mortality and morbidity. However, the function and regulation of global changes in histone acetylation and its relevance to cancer biology had been completely unknown. Recently, our group has revealed a novel role of chromatin and global histone acetylation as a regulator of intracellular proton load. We have shown that global histone deacetylation is coupled to the co-transport of acetate ions and protons out of the cell through the monocarboxylate transporters (MCTs), allowing for regulation of intracellular pH in acidic conditions. Conversely, histones are globally acetylated at alkaline pH to combat the increase in intracellular pH by sequestering acetate ions from co-transport out of the cell with available intracellular protons. Global deacetylation of histones at low pH requires continuous histone deacetylase (HDAC) activity as pharmacological inhibition of HDACs compromises pHi maintenance in acidic microenvironments. This proposal aims to determine the precise genome-wide distribution of changes in histone acetylation in response to changes in intracellular pH and the consequences for gene expression and cancer cell behavior. We will seek to elucidate the mechanism of pH-induced histone deacetylation and identify the main HDACs involved in regulating this process. Our data thus far suggest the implication of this novel function of global histone acetylation in cancer tissues. We postulate that cancer tissues displaying low histone acetylation levels, may be utilizing this mechanism to maintain a relatively alkaline pHi despite an acidic extracellular environment-a well-known hallmark of rapidly dividing cells. The findings of this research will reveal a novel dimension of chromatin biology and histone acetylation in integrating control of gene expression with cellular physiology. Furthermore, our work will provide new insight into more effective use of HDAC inhibitors (HDACi) in the clinic and has the potential to shine light on mechanisms of HDACi innate and acquired resistance in various types of cancer.