Monday, July 09, 2007

Histone deacetylase enzymes

You don't often hear histone deacetylase (HDAC) enzymes being discussed in ordinary conversation at cocktail parties or around the water cooler – unless perchance you stumble into a conversation among biomedical researchers.

But that might change a bit sometime in the not too distant future. HDAC and HDAC inhibitors are increasingly one of the "hot" topics in cancer research, and their importannce is now leaking out into a variety of disparate areas of biomedicine. There are even connections with other trendy topics, such as the SIR2 "longevity gene" and the NF-κB transcription factors.

Perhaps I should back up a moment and say a few words about histones and histone deacetylases. As you know, DNA generally does not float around all by itself inside a cell. With about 3 billion base pairs, human DNA, simply in order to fit into a cell in an orderly way, needs to be kept most of the time in a very compact form within the 23 chromosome pairs. The material making up chromosomes is called chromatin, which is made up of protein complexes called nucleosomes, around which the DNA is wound. Each nucleosome in turn is made up mostly of a core containing 8 histone proteins of several different types.

This arrangement has important implications for gene expression, because genes that occur in a portion of DNA that is wrapped tightly around a nucleosome are not readily available for translation into messenger RNA, which determines when and how proteins corresponding to the gene can be constructed. However, when an acetyl group is attached to one or more histones of a nucleosome, the DNA becomes less tightly bound, so that its genes can be more easily expressed.

Conversely, removing acetyl groups that may be attached to histones of the nucleosome largely inhibits access to the genes, effectively "silencing" them. A histone deacetylase is an enzyme that removes acetyl groups, so it is a mechanism for silencing groups of genes. About 11 HDACs (depending on how one counts) are known in higher eukaryotic cells.

This gene silencing is anything but a trivial function. For example, the proteins Sirtuin and Sir2 (Sirt1 in mammals), variations of which are found in most eukaryotic cells and are known to be involved with aging, are HDACs. On the other hand, cancer tumors frequently take advantage of HDACs to silence genes that would otherwise promote cancer cell death.

Because of the role of HDACs in cancer, an inhibitor of an HDAC is a potential anti-cancer drug. As we will see, there are a number of these now in clinical trials to fight various cancers – and one has even been approved by the FDA for use (Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA)).

For a great source of technical information on HDACs, especially in relation to cancer, check here.

Following are some research announcements pertaining to HDACs. They are mostly recent, and have been appearing at an increasing rate. Note how some of the most recent ones are in areas well outside of oncology.

Future Therapies For Stroke May Block Cell Death (6/14/07)
Substantial neurological damage occurs in strokes and neurodegenerative diseases like ALS, Parkinson's, and Huntington's. Researchers suspect that there are neuroprotective proteins whose expression could be increased to limit cell death if an inhibitor for the appropriate HDAC can be found.

At Penn, 'tantalizing' finds in cell research (6/14/07)
There are various neurodegenerative diseases which involve damaged or misfolded proteins that are toxic to cells. There is a mechanism called autophagy that is capable of disposing of such proteins, but it does not work fast enough in the presence of disease. Researchers have found that HDAC6 can facilitate autophagy and mitigate disease in a fruit fly model.

Gene Switched Off In Cancer Can Be Turned On, Researchers Discover (6/12/07)
A gene whose protein controls cell growth, called Brahma or BRM, is silent but not missing or mutated in some cancer cells. It is turned off in about 15 percent of tumors studied, including cells from lung, esophageal, ovarian, bladder, colon and breast cancers. HDAC inhibitors were found that could undo the silencing of the gene.

Cancer Drug Enhances Long-term Memory (6/6/07)
In a study with mice, researchers have shown that HDAC inhibitors together with a protein called CBP can enhance memory and actually strengthen neural connections in the hippocampus. CBP is known to relax chromatin, making gene expression easier in affected portions of DNA. Presumably the HDAC inhibitors prevent undoing the effect of CBP. Use of HDAC inhibitors alone did not have an effect on memory. If this effect exists in humans, CBP and HDAC inhibitors could be a therapy for people with Alzheimer's and Huntington's diseases and Rubenstein-Taybi syndrome.

Vorinostat Shows Anti-cancer Activity In Recurrent Gliomas (6/5/07)
Vorinostat is the first FDA approved oral anti-cancer agent that is an HDAC inhibitor. It has been shown to be effective as a treatment for cutaneous T cell lymphoma. This study indicates it also shows activity in patients with recurrent glioblastoma multiforme.

Eat Your Broccoli: Study Finds Strong Anti-Cancer Properties In Cruciferous Veggies (5/18/07)
Cruciferous vegetables such as broccoli, bok choy, and brussels sprouts contain significant amounts of sulforaphane, which has noteworthy anti-cancer properties. This research suggests that cruciferous vegetables have HDAC inhibiting effects, which might explain their anti-cancer properties.

Healthy Muscles: Scientists Identify Pathway That Promotes Muscle Cell Survival In Mice (5/1/07)
Mice genetically engineered with a defective protein called cAMP responsive element binding protein (CREB) have poorly developed muscles. This appears to be related to lack of inhibition of a specific HDAC enzyme when CREB is defective. Investigation revealed that production of an enzyme called salt-inducible kinase-1 (SIK1) is also inhibited in the presence of defective CREB. SIK1 was found to phosphorylate the HDAC protein, which inhibits its histone deacetylation capability. Further experimentation showed that raised SIK1 levels or use of other inhibitors of the HDAC enzyme also restored muscle cell health in the mice with defective CREB. The findings may lead to treatments for diseases that affect cell survival, such as muscular dystrophy, neurodegenerative diseases, and congestive heart failure.

Novel Drug Shows Potential For Treating Leukemia (4/21/07)
HDAC inhibitors, when used in combination with an experimental proteasome inhibitor drug, NPI-0052, were more effective at inhibiting the main enzymatic activity of the proteasome than NPI-0052 alone. Either alone or in combination NPI-0052 was much more effective than bortezomib (marketed as Velcade), the only FDA-approved proteasome inhibitor. Proteasomes clean out mutated or damaged proteins within cells, but in cancer cells this allows unwanted cell growth and reproduction. Proteasome inhibitors block this process, resulting in apoptosis of the malignant cells. Although bortezomib is effective for treating multiple myeloma and mantle cell lymphoma, it is ineffective by itself against leukemia, so NPI-0052 may be a good alternative.

Scientists Induce Cell Death In Leukemia (4/17/07)
The proteasome inhibitor bortezomib when used in combination with either of two HDAC inhibitors (romidepsin and belinostat) was shown in preclinical tests to be very lethal to cultures of human chronic lymphocytic leukemia cells. Other preclinical and clinical data suggest similar synergistic effects of bortezomib in additional cancer cell types.

Treatment Extends Survival In Mouse Model Of Spinal Muscular Atrophy (2/23/07)
Spinal muscular atrophy (SMA) is the most common severe hereditary neurological disease of childhood and is usually fatal. SMA is caused by mutations in a gene called SMN1. A related gene called SMN2 can sometimes produce the SMN protein, but in very small amounts. A drug called trichostatin A (TSA) is a potent HDAC inhibitor that is an antifungal antibiotic and has been found capable of increasing SMN protein production from the SMN2 gene in a mouse model and in cells from SMA patients. Improved survival was observed in the mouse model of SMA.

Two Drugs May Stabilize Plaques In Atherosclerosis (11/15/06)
An anti-fungal drug and an anti-cancer drug – TSA and SAHA (see references elsewhere in this report) – have been reported to decrease cholesterol deposits in the walls of arteries. In this case, the drugs appear to have an anti-inflammatory mechanism. The two compounds decreased inflammatory proteins produced by macrophages taken from normal mice. Such inflammatory proteins can make atherosclerotic plaque unstable. After the macrophages were treated with either TSA or SAHA, dramatic decreases were measured in LDL and total cholesterol in the macrophages. In addition, the drugs prevented macrophages from turning into foam cells inside arterial walls,

Researchers Make Advances In Attacking Leukemia Cells (10/21/05)
This somewhat older research demonstrated that in leukemia cells, HDAC inhibitors also induce changes in a master regulatory protein known as NF-κB, which is involved in regulation of inflammation, cell survival and many other functions. It was found that NF-κB inhibitors dramatically increased the lethality of HDAC inhibitors in various leukemia cell types. Such inhibitors are the subject of great interest as potential anti-inflammatory agents for use in various disorders, such as arthritis and inflammatory bowel disease. The research suggests they may also be valuable in enhancing the antileukemic efficacy of HDAC inhibitors, which have already shown antileukemic activity on their own.

MIT Researchers Uncover New Information About Anti-Aging Gene (2/18/00)
This is old and now well-known research by Leonard Guarente and associates, showing that an anti-aging gene, called Silent Information Regulator (SIR2), is an enzyme – specifically an HDAC enzyme. As such, SIR2 can silence genes in whole sections of a genome. As cells age, problems such as genome instability and inappropriate gene expression surface as genes that had always been turned off sometimes get turned on. SIR2 may forestall such age-related problems, which can lead to cell death. The research team found that yeast cells with an extra copy of SIR2 live longer, while yeast cells without SIR2 have a shorter lifespan. The connection with metabolism (and hence caloric restriction) may stem from a co-enzyme, called nicotinamide adenine dinucleotide (NAD), that is related to metabolism and is required for SIR2 to be activated.

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