Date of Award

1-1-2014

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xviii, 213 pages) : illustrations (some color)

Dissertation/Thesis Chair

Martin P Tenniswood

Committee Members

Douglas S Conklin, JoEllen Welsh, Randall H Morse, Thomas J Begley

Keywords

Functional Genomics, HDAC inhibitor, Histone acetyltransferase Gcn5, Iron, Oxidative stress, Yeast, Histone deacetylase, Enzyme inhibitors, Carcinogenesis, Antineoplastic agents

Subject Categories

Biology

Abstract

Epigenetic alterations are common in human cancers. Loss of histone acetylation occurs early in tumorigenesis, correlates with advanced stage and poor clinical outcome, and histone acetyltransferases (HATs) and histone deacetylases (HDACs) are aberrantly expressed or recruited to promoters in a variety of cancers. Histone deacetylase inhibitors (HDACis) are attractive anti-cancer therapeutics because of their selectivity for transformed cells and their ability to induce growth arrest, cell death, senescence and differentiation, enhance tumor immunogenicity and inhibit angiogenesis and invasion. However, many questions remain regarding their mechanism(s) of action. While monotherapy with HDACis for solid tumors is not effective, combination therapies show better responses. We have taken a combination approach of chemical-genetic and transcriptional profiling to identify gene products that modulate the response to HDAC inhibition, to gain insights into the mechanism of action and identify potential combination targets to enhance the anti-tumor effects of HDACis. In S. Cerevisiae, gene deletions that confer sensitivity to the HDAC inhibitor CG-1521 are highly enriched in processes regulating chromatin remodeling and transcription, including components of the SAGA histone acetyltransferase complex that contains the HAT Gcn5. Deletion of GCN5 confers sensitivity to CG-1521-induced cell death through accumulation of oxidative stress. Similarly, inhibition of the human homologues GCN5 and PCAF exacerbates the growth-inhibitory effect of CG-1521 in cancer cells. Taken together, our work suggests that the combination of selective HAT and HDAC inhibitors may be effective for the treatment of cancer. CG-1521 treatment also modulates the expression of genes involved in iron transport and homeostasis, which are regulated by the transcription factor Aft1, whose deletion confers sensitivity to CG-1521. In contrast to other hydroxamic acid based HDACis, iron abrogates the effects of CG-1521 in both yeast and cancer cells. These results indicate that, in addition to its effects on chromatin conformation and transcription, CG-1521 chelates iron and disrupts iron homeostasis, which may be responsible for a significant part of its growth-inhibitory properties. These findings have implications for the design of drug delivery and combination treatments and suggest that CG-1521 may be useful for the treatment of solid tumors and iron overload diseases.

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