Inhibition of Histone Deacetylases (HDACs)
In This Section:
HDACs in Normal Cells
The activity of proteins can be altered in several ways, including by chemical modification. Phosphorylation is one common type of modification. Another common modification is acetylation, in which acetyl chemical groups are added to proteins.
Acetylation--and deacetylation, the removal of acetyl groups--can influence the stability or function of proteins or alter their capacity to interact with other molecules.
One group of proteins that is frequently modified by acetylation is the histone family. Histones are proteins that interact closely with DNA and help package it inside the nucleus.
Genes located within regions of the tightly wound DNA that is associated with unacetylated histones are usually not expressed because the DNA is so tightly packaged that they are inaccessible to the cellular machinery that drives gene expression. Acetylation of histones loosens the close association between these proteins and DNA, thereby allowing the DNA structure to relax. Consequently, other proteins are able to reach the DNA and activate gene expression.
On the other hand, gene expression can be shut down if cellular enzymes called histone deacetylases, or HDACs, remove the acetyl groups from the histones.
Although named for their interaction with histones, HDACs participate in the regulation of acetylation of a wide variety of proteins that are involved in virtually all cellular processes.
HDACs in Cancer Cells
The activities and expression of many proteins implicated in cancer are regulated by acetylation. The importance of acetylation in cancer is illustrated by the finding that cancer cells cultured in the laboratory undergo cell cycle arrest and ultimately die when treated with HDAC inhibitors, whereas normal cells are relatively unaffected.
Inhibiting HDACs
The apoptotic death of myeloma cells in response to treatment with HDAC inhibitors is likely due to changes in the activities and expression of numerous proteins. For example, through their effects on histones, HDAC inhibitors are thought to promote expression of p21, a cell cycle inhibitor, and Bax, a protein that promotes apoptosis.
In addition, HDAC inhibitors affect the activity of HSP90, one of a number of cytoplasmic proteins regulated by acetylation. Acetylated HSP90 is unable to form stable complexes with its client proteins, leading to their degradation by proteasomes.
HDAC inhibitors in combination with standard chemotherapy or other targeted therapies are being tested in clinical trials of multiple myeloma.
More Information
HDAC Inhibitors
This table lists several HDAC inhibitors that have been or are being tested in clinical trials for multiple myeloma. To date, none of these agents have been approved by the FDA for treatment of multiple myeloma, although vorinostat has been approved for another cancer, cutaneous T-cell lymphoma. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.
| Research Name | Generic Name | Trade Name(s) | Drug Type | |
|---|---|---|---|---|
| HDAC Inhibitors | SAHA (suberoyl anilide hydroxamic acid) | Vorinostat | Zolinza® | Small molecule |
| PXD101 | Belinostat | -- | Small molecule | |
| MS-275 | Entinostat | -- | Small molecule | |
| LBH589 | Panobinostat | -- | Small molecule | |
| FK228 | Romidepsin (also called depsipeptide) | -- | Small molecule | |
| ITF2357 | -- | -- | Small molecule | |
| PCI-24781 | -- | -- | Small molecule | |
| Sodium phenylbutyrate | -- | -- | Small molecule |
Self Test
Questions
- Acetylation of proteins can:
- Reduce protein stability
- Modify protein-protein interactions
- Modify gene expression
- All of the above
Answers
- Correct Answer: d
- Reduce protein stability - Partially correct.
There is a better answer. - Modify protein-protein interactions - Partially correct.
There is a better answer. - Modify gene expression - Partially correct.
There is a better answer. - All of the Above - Correct.
Protein acetylation can influence protein stability and protein-protein interactions. Acetylation of histones can also have an effect on gene expression.
- Reduce protein stability - Partially correct.
