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Targeted Therapies for Multiple Myeloma Tutorial

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.

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.'

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.'

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.

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.

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.

This is a split-screen image with a mass of pink normal cells shown on the left and a mass of green tumor cells shown on the right. Small green dots representing HDAC inhibitors are shown surrounding both cell masses. The normal cells are viable, but several of the cancer cells have undergone apoptosis, which is indicated by small gray vesicles. The screen text reads, 'Inhibition of HDACs causes death of cancer cells.'

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.

A mass of green tumor cells is shown in the middle of the screen. The cells are surrounded by small purple dots representing HDAC inhibitors. Several of the tumor cells are undergoing apoptosis.

A close-up view of DNA associated with acetylated histones is shown. A green histone deacetylase protein associated with a green 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.'

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.

Small protein fragments are shown coming out of the end of the cylindrical proteasome complex. This represents the Akt protein being degraded by the proteasome because the HSP90 was unable to stabilize it.

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 NameGeneric NameTrade Name(s)Drug Type
HDAC InhibitorsSAHA (suberoyl anilide hydroxamic acid)VorinostatZolinza®Small molecule
 PXD101Belinostat--Small molecule
 MS-275Entinostat--Small molecule
 LBH589Panobinostat--Small molecule
 FK228Romidepsin (also called depsipeptide)--Small molecule
 ITF2357----Small molecule
 PCI-24781----Small molecule
 Sodium phenylbutyrate----Small molecule


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. Reduce protein stability - Partially correct.
      There is a better answer.
    2. Modify protein-protein interactions - Partially correct.
      There is a better answer.
    3. Modify gene expression - Partially correct.
      There is a better answer.
    4. 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.