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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，这些发现已被多个其他实验室独立验证。然而，组蛋白乙酰化的整体变化在正常生物学中的功能以及它如何影响癌症表型还完全未知。我们提出的证据表明，全球组蛋白乙酰化和脱乙酰化耦合到乙酸和质子进出细胞的共运输，有效地使染色质成为细胞内质子负荷的调节剂，因此，细胞内pH值（pHi）。在酸性条件下，组蛋白被整体脱乙酰化，并且所得到的乙酸酯分子与质子通过单羧酸转运蛋白（MCT）共转运出细胞，从而降低细胞内质子负荷。在碱性pH下，组蛋白被整体乙酰化，用于储存乙酸分子并抵抗pH的进一步增加。组蛋白在低pH下的去乙酰化需要连续的组蛋白去乙酰化酶（HDAC）活性，并且不是由于HAT活性受损。抑制HDAC或MCT以分别降低乙酸盐可用性或输出，降低了pH，特别是损害了酸性微环境中的pH维持。因此，组蛋白乙酰化作为变阻器来调节pHi。我们的数据表明HDAC抑制剂的一种新的作用机制，并提高了显示低水平组蛋白乙酰化的癌组织可能分泌乙酸盐和质子以维持相对于细胞外环境的碱性pHi的可能性-这是快速分裂细胞的标志。在本申请中，我们的目标是确定组蛋白乙酰化响应pH的全局变化如何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诱导的组蛋白去乙酰化的机制，并鉴定转运HDAC从染色质释放的乙酸分子的主要MCT。我们还将确定组蛋白乙酰化响应pH的全局变化如何影响癌细胞的致瘤性。最后，我们将在完全注释的原发性癌组织中将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服务的功能增加一个新的维度。