IRIC - Institute for Research in Immunology and Cancer

Published on February 13, 2012

DNA is usually represented as a long linear molecule (the famous double helix). In fact, in the cell nucleus, DNA is generally spooled around histone proteins to form more compact structures called nucleosomes. Each nucleosome contains DNA and an octamer of histones composed of two molecules of each type of histone: H2A, H2B, H3 and H4. The interaction of DNA with nucleosomes is regulated by different chemical modifications of histones (phosphorylation, methylation, acetylation, etc.) that play important roles in a number of processes that require access to DNA.

The laboratories of Pierre Thibault and Alain Verreault at IRIC, and their colleagues in the Department of Biochemistry at the University of Montreal, have developed analytical techniques to quantify precisely different types of histone modifications. This technical breakthrough has led to surprising observations that question the links between certain histone modifications and cancer. Their findings were recently published in the journal Scientific Reports of the Nature Publishing Group.
The different types of modifications include reversible acetylation (addition of a COCH3 group) of specific histone lysine residues. Among other roles, histone acetylation is important for gene transcription and repair of DNA damage induced by many compounds used in cancer chemotherapy. The acetylation and deacetylation of lysine residues are respectively catalyzed by enzymes known as histone acetyl transferase (HATs) and histone deacetylases (HDACs). Several chemical compounds that inhibit HDACs (HDACi) have shown interesting anti-proliferative properties and are currently in clinical trials or, in a few cases, approved for the treatment of certain types of cancer.
The mode of action of HDACi remains poorly understood and it is therefore crucial to determine whether histones are the key targets responsible for the therapeutic properties of HDACi. It is also important to determine which specific sites of acetylation are affected by the presence of HDACi. For example, it was recently suggested that the acetylation of lysine 56 in histone H3 (H3K56ac) was a diagnostic and prognostic marker for several cancers.
The techniques of quantitative mass spectrometry developed by IRIC researchers have revealed that, even in cancer cells, H3K56ac is a very rare histone modification whose abundance remains unchanged when cells are treated with HDACi. Their results also indicate that the antibodies previously used to study H3K56ac were not specific. These studies question the dogma that there is a link between H3K56ac and cancer. In addition, IRIC researchers showed that HDACi approved for the treatment of certain types of lymphoma (a cancer of white blood cells) lead to hyperacetylation of the majority of histone H3 and H4 molecules. However, this hyperacetylation occurs equally well in normal cells and cancer cells.
These results raise an important issue for future investigation. Are the therapeutic effects of HDACi induced by hyperacetylation of histones or by hyperacetylation of other proteins?

Paper Cited

Drogaris P, Villeneuve V, Pomiès C, Lee E-H, Bourdeau V, Bonneil É, Ferbeyre G, Verreault A, Thibault P. (2012). Histone Deacetylase Inhibitors Globally Enhance H3/H4 Tail Acetylation Without Affecting H3 Lysine 56 Acetylation. Scientific Reports. 2:220