Dynamics of Histone Acetylation in Cancer Cell Physiology

癌细胞生理学中组蛋白乙酰化的动态

基本信息

批准号：
8563238
负责人：
Siavash Kurdistani
金额：
$ 31.96万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8563238
关键词：
Acetates Acetyl Coenzyme A Acetylation Address Affect Anchorage-Independent Growth Appearance Biological Process Biology Cell Culture Techniques Cell membrane Cell physiology Cells ChIP-seq Chemicals Chromatin Clinical Clinical Data Coupled Cues DNA Data Deacetylation Dimensions Effectiveness Environment Gene Expression Gene Expression Regulation Genome Genomics Global Change Growth Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone Deacetylation Histones Intercistronic Region Kinetics Laboratories Link Lysine Maintenance Malignant Neoplasms Malignant neoplasm of prostate Maps Measures Messenger RNA Metabolic Methylation Molecular Morbidity - disease rate Normal Cell Normal tissue morphology Outcome Phenotype Physiological Process Property Proteins Protons Proxy RNA Recurrence Regulation Relative (related person)Renal carcinoma Site Spatial Distribution Tissue Microarray Tissues Work Yeasts base cancer cell cancer type clinically relevant experience extracellular follow-up histone modification improved in vivo man mortality neoplastic cell novel prevent prognostic promoter public health relevance response tumor tumorigenic

项目摘要

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.

描述（由申请人提供）：我们的实验室发现，组蛋白乙酰化整体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着增加，这一发现已被多个其他实验室独立验证。然而，正常生物学中组蛋白乙酰化的整体变化的功能以及它如何影响癌症表型还完全未知。我们提供的证据表明，整体组蛋白乙酰化和脱乙酰化与进出细胞的乙酸盐和质子的共同转运有关，有效地使染色质成为细胞内质子负荷的调节剂，从而调节细胞内的 pH (pHi)。在酸性条件下，组蛋白整体脱乙酰化，产生的乙酸盐分子通过单羧酸转运蛋白 (MCT) 与质子共同转运出细胞，从而减少细胞内质子负荷。在碱性 pH 条件下，组蛋白被全面乙酰化，用于储存乙酸盐分子并抵抗 pHi 的进一步增加。低 pH 条件下组蛋白的脱乙酰化需要持续的组蛋白脱乙酰酶 (HDAC) 活性，而不是由于 HAT 活性受损。抑制 HDAC 或 MCT 分别降低乙酸盐的利用率或输出，会降低 pHi，尤其会影响酸性微环境中 pHi 的维持。因此，组蛋白乙酰化起到变阻器的作用来调节 pHi。我们的数据表明 HDAC 抑制剂有一种新的作用机制，并提出了一种可能性，即组蛋白乙酰化水平较低的癌症组织可能会分泌乙酸盐和质子来维持相对于细胞外环境的碱性 pHi，这是细胞快速分裂的标志。在此应用中，我们的目标是确定组蛋白乙酰化的整体变化如何响应 pH 值映射到基因组的特定区域以及对基因表达的影响。我们将确定 pH 诱导的组蛋白脱乙酰化的机制，并确定转运 HDAC 从染色质释放的乙酸盐分子的主要 MCT。我们还将确定组蛋白乙酰化响应 pH 值的整体变化如何影响癌细胞的致瘤特性。最后，我们将在完全注释的原发性癌症组织中将 MCT 的表达、HDAC 的定位和整体组蛋白乙酰化水平联系起来，以确定其临床相关性。我们的发现。我们的工作将为染色质和组蛋白乙酰化为细胞提供的功能增加一个新的维度。