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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Okano, Paul
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Park, Jung Wook; Lee, John K; Sheu, Katherine M et al. (2018) Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science 362:91-95
Xue, Yong; Pradhan, Suman K; Sun, Fei et al. (2017) Mot1, Ino80C, and NC2 Function Coordinately to Regulate Pervasive Transcription in Yeast and Mammals. Mol Cell 67:594-607.e4
Nguyen, Andrew H; Elliott, Irmina A; Wu, Nanping et al. (2017) Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts. Oncotarget 8:19074-19088
Huang, Chengyang; Su, Trent; Xue, Yong et al. (2017) Cbx3 maintains lineage specificity during neural differentiation. Genes Dev 31:241-246
Xue, Yong; Schmollinger, Stefan; Attar, Narsis et al. (2017) Endoplasmic reticulum-mitochondria junction is required for iron homeostasis. J Biol Chem 292:13197-13204
Wang, Wenyuan; Org, Tonis; Montel-Hagen, Amélie et al. (2016) MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis. Nat Commun 7:12376
Pradhan, Suman K; Su, Trent; Yen, Linda et al. (2016) EP400 Deposits H3.3 into Promoters and Enhancers during Gene Activation. Mol Cell 61:27-38
Xue, Yong; Van, Christopher; Pradhan, Suman K et al. (2015) The Ino80 complex prevents invasion of euchromatin into silent chromatin. Genes Dev 29:350-5
Kurdistani, Siavash K (2014) Chromatin: a capacitor of acetate for integrated regulation of gene expression and cell physiology. Curr Opin Genet Dev 26:53-8