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CancerQuest > Introduction to Patient Information > An Introduction to Cancer Treatments > Targeted Therapy > Histone Acetylases (HATs) and Histone Deacetylases (HDACs)
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Histone Acetylases (HATs) and Histone Deacetylases (HDACs)

With few exceptions, such as red blood cells, all of our cells contain two full copies of our genome. Each chromosome is composed of a single piece of double-stranded DNA containing millions or even hundreds of millions of nucleotide pairs. These molecules are very thin and extremely long. Each cell contains approximately 2 meters (~6 feet) of DNA. All of this DNA must be packaged in such a way that it fits into the cell nucleus, a very small space. To accomplish this feat, the negatively charged DNA is condensed and tightly wrapped around positively charged proteins called histones.(1) Eight histone proteins (two copies each of four different proteins) form a core around which the DNA winds. The histone proteins, along with the DNA wrapped around it, form a structure called a nucleosome. Each nulceosome holds only about 150 base pairs of DNA so there are thousands of these structures along the length of each chromosome. As shown in the figure below, the nucleosomes are connected together by small stretches of DNA and look like beads on a string. Nucleosomes can further condense in the presense of additional, non-histone proteins to form chromatin.(2)

The ability of a particular transcription factor to bind to its target gene is, in part, dependent on modifications that are made to the histone proteins. Enzymes called histone acetyl transferases (HATs) alter the chromatin (DNA:protein) structure by adding short carbon chains to some histone proteins. This alteration changes the structure of the DNA:histone interaction loosening up the 'bead', allowing transcription factors to bind. A separate group of enzymes, histone deacetlyases (HDACs), is responsible for removing the acetyl groups from the histones, shutting down transcription.

When the histones are deacetylated, the positive charges are restored and the DNA binds more tightly to the nucleosome. Deacetylation leads to a repression of transcription because the necessary transcription factors, regulatory factors, and RNA polymerase complex are unable to gain access to the DNA. (3)

Abnormal activity of HDACs has been observed in several different types of cancer, such as acute promyelocytic leukemia, acute myelogenous leukemia, non-Hodgkin lymphoma, and some types of colorectal and gastric carcinomas. When these enzymes act incorrectly, they can prevent the transcription of key genes. This process appears to be an important step in the tumorigenic process in some forms of cancer.(4) (5)

HDAC inhibitors have been shown to alter the growth of several different forms of cancer.(5) These molecules, many of which have been isolated from natural sources, have demonstrated the ability to inhibit proliferation, induce differentiation, and cause apoptosis in tumor cells. Histone deacetylases (HDACs) may have other roles in gene expression. Research has shown interactions between HDACs and proteins that directly regulate gene expression. They also have been shown to interact with transcription factors themselves. (6) All of these activities demonstrate the important role that HDAC plays in the regulation of transcription in the cell.

One exciting feature of the HDAC inhibiting drugs is that they have demonstrated little toxicity in preliminary tests. Although much of the testing for these potential therapies has been performed only in cell culture and animal models, the results of these tests have been very promising and several clinical trials are underway as a result. HDAC inhibitors have been shown to affect many different types of solid and hematological cancers in research studies, including neuroblastoma, melanoma, leukemia (including APL and myeloid), breast cancer, prostate cancer, lung cancer, ovarian cancer, and colon cancer.(5)

HDAC inhibitors are grouped into categories based on their chemical structures. The exact mechanism through which these compounds work is still poorly understood, but is a focus of current research. It is thought, though, that each inhibitor acts to inhibit a specific HDAC; this in turn has a specific effect upon gene expression, cell cycle regulation, proliferation, differentiation, and apoptosis. Scientists also believe that HDAC inhibitors cause changes in the cytoskeleton, which further aids in their anti-tumor activity. Many of these compounds are effective in very low doses and appear to act upon specific regions of the genome, altering the transcription of only select sets of genes. The true efficacy of HDAC inhibitors is yet to be determined, in testing they have shown the potential to be effective, selective treatments for some forms of cancer. These compounds may be used in combination with other anti-cancer agents.(5)

The FDA approved a HDAC inhibitor in 2006: Vorinostat (Zolinza®)

There are several new drugs under investigation(7)

View a list of clinical trials of HDAC inhibitors (NCI).

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Last Modified: 12/02/2011 Print Email Page
References for this page:
  1. Hua J and Muschel RJ. "Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system." Cancer Res (1996). 56: 5279-82. [PUBMED]
  2. Ribozyme Pharmaceuticals [http://www.rpi.com]
  3. Scanlon KJ, et al. "Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein." PNAS (1991). 88 (23): 10591-5. [PUBMED]
  4. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. "Histone deacetylases and cancer: causes and therapies." Nat Rev Cancer (2001). 1(3): 194-202. [PUBMED]
  5. Richon VM, O'Brien JP. "Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment." Clin Cancer Res (2002). 8(3): 662-4. [PUBMED]
  6. Ohta Y, et al. "H-ras ribozyme-mediated alteration of the human melanoma phenotype." Ann NY Acad Sci (1994). 716: 242-53. [PUBMED]
  7. Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009 Nov 10;27(32):5459-68. Epub 2009 Oct 13. [PUBMED]
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