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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 called acetylation, in which acetyl chemical groups are added to proteins.

A close-up view of a blue protein in the cytoplasm of a normal cell is shown. The protein is linked to three red globular structures representing acetyl groups. The image is labeled 'Acetylation.'

A close-up view of a blue protein in the cytoplasm of a normal cell is shown. The protein is linked to three red globular structures representing acetyl groups. The image is labeled “Acetylation.”

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.

A close-up view of a blue protein in the cytoplasm of a normal cell is shown. The three red globular structures representing acetyl groups have dissociated from the protein. The image is labeled 'Deacetylation.'

A close-up view of a blue protein in the cytoplasm of a normal cell is shown. The three red globular structures representing acetyl groups have dissociated from the protein. The image is labeled “Deacetylation.”

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.

A close-up view of a strand of DNA is shown. The yellow DNA is wrapped around several blue protein complexes labeled 'Histones.'

A close-up view of a strand of DNA is shown. The yellow DNA is wrapped around several blue protein complexes labeled “Histones.”

Genes located within regions of DNA associated with unacetylated histones are usually not expressed because the DNA is so tightly packaged it is 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.

A close-up view of DNA wrapped around two histone complexes is shown. Several acetyl groups are linked to the histones. A protein complex representing the cellular machinery that drives gene expression is associated with the DNA between two histones.

A close-up view of DNA wrapped around two histone complexes is shown. Several acetyl groups are linked to the histones. A protein complex representing the cellular machinery that drives gene expression is associated with the DNA between two histones.

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.

A close-up view of DNA associated with histones is shown. Green proteins representing histone deacetylases are associated with the histones and acetyl groups are shown moving away from the histones. The cell's gene expression machinery is moving away from the DNA.

A close-up view of DNA associated with histones is shown. Green proteins representing histone deacetylases are associated with the histones and acetyl groups are shown moving away from the histones. The cell's gene expression machinery is moving away from the DNA.

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. Acetylation appears to play an important role in cutaneous T cell lymphomas, or CTCLs, which are non-Hodgkin lymphomas that affect the skin. Whereas most normal cells are relatively unaffected by HDAC inhibitors, these drugs induce apoptosis of CTCL cell lines and peripheral blood lymphocytes from CTCL patients.

This is a split-screen image. On the left is a mass of normal cells and on the right is a mass of tumor cells. Both types of cells are being treated with HDAC inhibitors represented by small purple molecules. The normal cells appear to be unaffected by the HDAC inhibitors, but several of the cancer cells are undergoing apoptosis, evidenced by the fact that they are splitting into gray globules. Screen text reads, 'Inhibition of HDACs causes death of CTCL cells.'

This is a split-screen image. On the left is a mass of normal cells and on the right is a mass of tumor cells. Both types of cells are being treated with HDAC inhibitors represented by small purple molecules. The normal cells appear to be unaffected by the HDAC inhibitors, but several of the cancer cells are undergoing apoptosis, evidenced by the fact that they are splitting into gray globules. Screen text reads, 'Inhibition of HDACs causes death of CTCL cells.'

Inhibiting HDACs

The apoptotic death of CTCL cells in response to HDAC inhibitors is likely due to changes in the activities and expression of multiple 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.

A close-up view of DNA associated with acetylated histones is shown. A green histone deacetylase protein associated with a purple molecule representing an HDAC inhibitor is shown near the DNA. One section of DNA is glowing, indicating that the genes in this region are being expressed. The glowing DNA is labeled 'Expression of p21 and Bax genes.'

A close-up view of DNA associated with acetylated histones is shown. A green histone deacetylase protein associated with a purple molecule representing an HDAC inhibitor is shown near the DNA. One section of DNA is glowing, indicating that the genes in this region are being expressed. The glowing DNA is labeled “Expression of p21 and Bax genes.”

HDAC inhibitors also affect the activity of a number of cytoplasmic proteins that are regulated by acetylation. One HDAC inhibitor, Zolinza® (vorinostat), has been approved by the FDA for treatment of patients with CTCL that has progressed, persisted, or recurred during or after two systemic therapies.

A male patient is shown sitting on a hospital bed. A health care professional is standing at the side of the bed.

Zolinza® (vorinostat) and other HDAC inhibitors are currently being studied in clinical trials of CTCL and other types of lymphoma.

Several green figures are shown in the background. Five gray ovals labeled Phase 0, Phase I, Phase II, Phase III, and Phase IV are shown in the upper left-hand corner. Screen text reads, 'HDAC inhibitors are being tested in clinical trials of lymphoma.'

Several green figures are shown in the background. Five gray ovals labeled “Phase 0,” “Phase I,” “Phase II,” “Phase III,” and “Phase IV” are shown in the upper left-hand corner. Screen text reads, “HDAC inhibitors are being tested in clinical trials of lymphoma.”

More Information

This table lists several HDAC inhibitors that are being tested in clinical trials for lymphoma.

 Research NameGeneric NameTrade NameDrug Type
HDAC inhibitorsSAHA (suberoyl anilide hydroxamic acid)VorinostatZolinza®Small molecule
 PXD101Belinostat--Small molecule
 SNDX-275
MS-275
Entinostat--Small molecule
 LBH589Panobinostat--Small molecule
 FK228Romidepsin (also called depsipeptide)--Small molecule
 ITF2357----Small molecule
 PCI-24781----Small molecule
 Sodium phenylbutyrate----Small molecule

Drugs that have been approved by the FDA for treatment of lymphoma are marked with an asterisk. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

Self Test

Questions

  1. Acetylation of proteins can:
    1. Reduce protein stability
    2. Modify protein-protein interactions
    3. Modify gene expression
    4. All of the above

Answers

  1. Correct Answer: d
    1. Partially correct.
      There is a better answer.
    2. Partially correct.
      There is a better answer.
    3. Partially correct.
      There is a better answer.
    4. Correct.
      Protein acetylation can influence protein stability and protein-protein interactions. Acetylation of histones can also have an effect on gene expression.