Two Epigenetic Targets Are More Effective Than One

Lysine-specific histone demethylase 1 (LSD1) via Wikimedia Commons

Epigenetics is a new and exciting territory to explore as we understand more about the role it plays in gene silencing and expression. Because epigenetic regulation of gene expression is caused by specific modification of histone proteins (e.g., methylation) that play a role in disease states like cancer, enzymes like histone deacetylases (HDACs) become viable drug targets. One drawback to inhibiting proteins that modify histones is even when selectively targeting HDACs, the effects can be far ranging with multiple HDAC-containing protein complexes found throughout the cell. These broad effects minimize the effectiveness of an inhibitor, caught between efficacy and toxicity. A recent article in Nature Communications explored how using a single compound to target two epigenetic enzymes was more effective than any individual inhibitor or combination of inhibitors. Continue reading

Rewriting the Histone Code: Searching for Treatments for Stage IV Thyroid Cancers

Chromatin fiberOften a diagnosis of thyroid cancer is associated with a good prognosis and fairly straightforward surgical treatments to remove the tumor followed by radioactive iodine ablation. Such treatment works well in tumors that have not metastasized and retain enough of their thyroid cell “identity” that they can still accumulate radioactive iodine.

However, aggressive thyroid cancers, which often metastasize and recur, do not respond to standard treatments because they are generally too dedifferentiated to accumulate iodine, so alternative treatments are needed.

One approach is to look for compounds that will reverse dedifferentiation, making tumor cells more likely to take up and concentrate radioactive iodine regardless of their location in the body. One possible target to effect dedifferentiation is epigenetic modification of histone proteins.

Histone proteins are more than the structural components of the nucleosome that organizes the chromatin inside cells. Histone proteins are subject to a host of protein modifications on their N-terminal tails such as acetylation, phosphorylation, methylation, ubiquitination and ADP-ribosylation. These various modifications are seen as creating a “histone code” that is read by other proteins and protein complexes (1). This code regulates patterns of gene expression and activity for a cell—in part resulting in a differentiated phenotype. Previous studies have suggested that some histone deacetylase (HDAC) inhibitors (e.g., valproic acid) can reverse some of the dedifferentiation associated with aggressive cancers (2).

Jang, et al. in a recent paper (3) published in Cancer Gene Therapy synthesized a group of HDAC inhibitor analogs (AB1–AB13) and tested them for their ability to inhibit growth of three aggressive human thyroid cancer cell lines and induce partial re-differentiation to the thyroid cell phenotype. Continue reading

Histones and Histone Deacetylases

Epigenetics is an increasingly big deal in biological discovery. We are regularly reading about the influence of actions peripheral to DNA in regulating DNA transcription and translation. We are learning that mice may fear what grandparent mice feared (Kelly’s blog ), due to heritable changes in DNA. In term of one of several mechanisms of epigenetic change, we are learning much about histone deacetylases and their role in gene regulation, as well as disease (Isobel’s blog ). In this blog, let’s take a step back and look at histones, and how they are influenced by acetylation/deacetylation.

The Role of Histones
Histones are proteins found in the nucleus of eukaryotic cells, where they package DNA into nucleosomes. Histones make up the main protein component of chromatin, acting as spool-like structures around which DNA wraps.

There are five major histone classes,three of these are core histones, the other two are called linker histones. Core histones comprise the core of the nucleosome, around which DNA is wrapped, while the linker histones bind at the entrance and exit sites of the DNA, so as to lock it into place. The linker histones also enable a higher order of structure. If you hold both ends of a rubber band, and twist one end, you’ll see that the rubber band twists and folds over itself; the end being held steady enables this twisting and folding: this is how the linker histones work. Histone-DNA structure is frequently represented as a beaded chain-type image (see figure).

DNA wrapping around histones in a bead and chain-like fashion.

DNA wrapping around histones in a bead and chain-like fashion.

Histone and DNA: Charged Interactions
Histone tails normally carry a positive charge due to amine groups present on their lysines and arginines. This positive charge is the means by which histone tails interact with and bind to the negatively-charged phosphate groups on the DNA backbone.

Histones are subject to post-translational modifications, primarily on their N-terminal tails, by enzymes. Such modifications include methylation, citrullination, acetylation, phosphorylation, SUMOylation, ubiquitination, and ADP-ribosylation. Such modifications can affect histone function in gene regulation. Acetylation is one of the most common post-translational modifications of histones (1). Continue reading