Histone Deacetylases (HDACs) and Cancer

HDACs in Cancer - Histone_Structure_A-01-1

Fig. 1: Structure of a mono nucleosome

Histon Deactetylases (HDACs) are overexpressed and show very high activities in a number of tumor cells. Expression of HDAC1, -5, and -7 can be even used as a cancer biomarker. Moreover, they play a crucial role in oncogene expression.

HDACs remove acetyl groups from N acetyl lysine residues in histones. These enzymes belong to a number of enzymes which control the condensation status of nucleosomes (structure of a mono nucleosome is shown in Fig.1). While acetylation of histones by Histone acetyltransferases leads to decondensation and thus allows DNA binding proteins to interact with exposed sites to activate gene transcription, the activity of HDACs allows histones to wrap the DNA more tightly.

HDAC classes

Four classes of HDACs can be differentiated all of which are available in active form through BPS Bioscience:

HDACs and cancer

HDAC 3 results - HDACs in Cancer

Fig. 2: Time course of HDAC3 activity against different concentration of SAHA (Vorinostat). HDAC3 activity is measured using the Kinetic HDAC3 Assay Kit (Cat. nr 14953003). Fluorescence was measured using a Tecan fluorescent microplate reader.

Knockdowns of HDACs in certain tumor types lead to induced apoptosis and cell cycle arrest. Deacetylation of p53 (a tumor suppressor) results in a decrease of transciptional activity. Furthermore, HDAC activity can result in upregulation of oncogenes such as BCL2. These results and a plethora of further findings (for a summary see West and Johnstone, JCI 124.1: 30-39 [2014]) made HDACs a very important target for cancer drug screening activities. Already in 2006, Vorinostat was the first HDAC inbibitor which has been approved  to treat CTCL (cutaneous T cell lymphoma) after preceding treatments have failed. The drug exhibits inhibitory effects on HDAC1, 2, 3, and 6. The second HDAC inhibitor approved has been Istodax, again a drug to treat CTCL. Numerous efforts are still underway to develop more HDAC inhibitors to fight cancer.

For inhibitor screening campaigns, convenient assays are needed. A comprehensive range of assays against all relevant HDAC enzymes have been recently developed – a complete overview is available here: HDAC inhibitor screening assays. Typical results obtained with the HDAC inhibitor Vorinostat (SAHA) are shown in Fig. 2.

Modulating HDACs

Modulating HDACs - Structure of Apicidin

Fig. 3: Structure of Apicidin

To characterize and differentiate different members of the HDAC family and to have reference inhibitors for drug screening, well defined modulators are needed. These compounds can either inhibit specific HDACs or show more general effects. Focus Biomolecules offers a range of high quality compounds, such as MS-275, Apicidin, Trichostatin A, BML-210, SAHA (Vorinostat), M-344, Tubastatin A•HCl, HPA (Hexyl-4-pentynoic acid), Na Valproate,Panobinostat,Phenylbutyrate Na, and Romidepsin.

If you are interested to learn more about our comprehensive offer of enzymes, activity assays and modulators, please contact me with the form below.

Written by Ali El Baya, PhD
Ali el Bayâ is the Sales Manager at tebu-bio for the North of Europe.