Dynamics of Global Histone Acetylation in Regulating Intracellular pH

描述（由申请人提供）：我们小组首次描述了整体组蛋白乙酰化在癌症中的预后价值，并已被多个其他实验室独立验证。这些报告发现，在癌症组织中，较低的整体组蛋白乙酰化水平与癌症相关的死亡率和发病率显著相关。然而，组蛋白乙酰化的全局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，我们的研究小组揭示了染色质和全局组蛋白乙酰化作为细胞内质子负荷调节因子的新作用。我们已经证明，整体组蛋白去乙酰化与醋酸离子和质子通过单羧酸转运体（mct）共同运输出细胞，从而允许在酸性条件下调节细胞内pH。相反，组蛋白在碱性条件下整体乙酰化，通过隔离醋酸离子与可用的细胞内质子共转运出细胞来对抗细胞内pH值的增加。低pH下组蛋白的整体去乙酰化需要持续的组蛋白去乙酰化酶（HDAC）活性，因为HDAC的药理抑制会损害酸性微环境中pHi的维持。本研究旨在确定组蛋白乙酰化在响应细胞内pH变化时的精确全基因组分布，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，我们的数据表明了这种整体组蛋白乙酰化在癌症组织中的新功能的含义。我们假设显示低组蛋白乙酰化水平的癌症组织可能利用这一机制来维持相对碱性的pHi，尽管酸性的细胞外环境是一个众所周知的快速分裂细胞的标志。这项研究的发现将揭示染色质生物学和组蛋白乙酰化在整合基因表达控制与细胞生理学中的一个新的维度。此外，我们的工作将为在临床中更有效地使用HDAC抑制剂（HDACi）提供新的见解，并有可能揭示各种类型癌症中HDACi先天和获得性耐药的机制。

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.