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.

Public Health Relevance

Histones are the main protein constituent of chromatin-the physiological relevant form of the genome. Chemical modifications of histones regulate normal processes that are based on DNA but are altered in cancer. This study aims to understand how alterations in levels of histone modifications contribute to cancer cell physiology and progression which can be used to improve the effectiveness of certain chemotherapeutics such as HDAC inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA178415-01
Application #
8563238
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Okano, Paul
Project Start
2013-09-23
Project End
2018-07-31
Budget Start
2013-09-23
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$319,550
Indirect Cost
$112,050
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095