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：
8739627
负责人：
Siavash Kurdistani
金额：
$ 31万
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/8739627
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，具有较低全球组蛋白乙酰化水平的癌组织显示出肿瘤复发率显着提高或与癌症相关的死亡率，这些发现已由其他多个实验室独立验证。然而，正常生物学中组蛋白乙酰化的全球变化及其对癌症表型的贡献的功能是完全未知的。我们提供了证据表明，全球组蛋白乙酰化和脱乙酰化与乙酸和质子的共转移和质子的共转移相结合，从而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（PHI）的调节剂。在酸性条件下组蛋白是全局脱乙酰化的，所得的乙酸盐分子通过单羧酸酯转运蛋白（MCT）与质子一起转运，从而降低细胞内质子载荷。在碱性pH值下，组蛋白是全球乙酰化的，用于储存乙酸盐分子并抵抗PHI的进一步增加。在低pH下，组蛋白的脱乙酰化需要连续的组蛋白脱乙酰基酶（HDAC）活性，而不是由于HAT活性受损而引起的。抑制HDAC或MCT分别降低乙酸盐的可用性或出口，降低了PHI，特别是损害了酸性微环境中的PHI维持。因此，组蛋白乙酰化是调节PHI的恒河体的作用。我们的数据表明，HDAC抑制剂的一种新型作用机理，并提高了表现低水平的癌组织O组蛋白乙酰化的可能性可能是分泌醋酸盐和质子，以维持碱性PHI相对于细胞外环境 - 迅速分裂的细胞的标志。在此应用中，我们旨在确定对基因组特定区域的pH图响应组蛋白乙酰化的全局变化以及基因表达的后果。我们将确定pH诱导的组蛋白脱乙酰基的机制，并确定运输HDACS从染色质释放的乙酸分子的主要MCT。我们还将确定响应pH的组蛋白乙酰化的全球变化如何影响癌细胞的致瘤性特性。最后，我们将联系全面注销的原发性癌症组织中MCT的表达，HDAC的定位和全球组蛋白乙酰化水平，以确定确定的临床相关性我们的发现。我们的工作将为染色质的功能和组蛋白乙酰化提供一个新的维度。