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Updated: Nov 3, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone deacetylase 2 selective inhibitors: A versatile therapeutic strategy as next generation drug target in cancer
Manasa Gangadhar Shetty1, Padmini Pai1, Renita Esther Deaver2
1Department of Biophysics, Manipal School of Life Sciences, MAHE, Manipal, India.
Abstract:
Acetylation and deacetylation of histone and several non-histone proteins are the two important processes amongst the different modes of epigenetic modulation that are involved in regulating cancer initiation and development. Abnormal expression of histone deacetylases (HDACs) is often reported in various types of cancers. Few pan HDAC inhibitors have been approved for use as therapeutic interventions for cancer treatment including vorinostat, belinostat and panobinostat. However, not all the HDAC isoforms are abnormally expressed in certain cancers, such as in the case of, ovarian cancer where overexpression of HDAC1-3, lung cancer where overexpression of HDAC 1 and 3 and gastric cancer where overexpression of HDAC2 is seen. Therefore, pan-inhibition of HDAC is not an efficient way to combat cancer via HDAC inhibition. Hence, isoform-selective HDAC inhibition can be one of the best therapeutic strategies in the treatment of cancer. In this context since aberrant expression of HDAC2 largely contributes to cancer progression by silencing pro-apoptotic protein expressions such as NOXA and APAF1 (caspase 9-activating proteins) and inactivation of tumor suppressor p53, HDAC2 specific inhibitors may help to develop not only the direct targets but also indirect targets that are crucial for tumor development. However, to develop a HDAC2 specific and potent inhibitor, extensive knowledge of its structure and specific functions is essential. The present review updates details on the structural features, physiological functions, and roles of HDAC2 in different types of cancer, emphasizing the challenges and status of the development of HDAC2 selective inhibitors against various types of cancer.
Insights
Histone deacetylase inhibitors (HDACi) are used in cancer therapy. However, targeting all HDAC isoforms is inefficient; HDAC2-specific inhibitors offer a promising, targeted approach for cancer treatment.
Area of Science:
- Epigenetics
- Cancer Biology
- Pharmacology
Background:
- Epigenetic regulation through histone and non-histone protein acetylation/deacetylation is crucial in cancer.
- Abnormal expression of histone deacetylases (HDACs) is common in various cancers.
- Approved pan-HDAC inhibitors exist, but isoform-specific targeting is needed due to varied HDAC expression across cancer types.
Purpose of the Study:
- To review the structural features, physiological functions, and roles of HDAC2 in cancer.
- To highlight the challenges and current status of developing HDAC2-selective inhibitors.
- To emphasize HDAC2-specific inhibition as a potential therapeutic strategy.
Main Methods:
- Literature review of HDAC2 structure, function, and role in cancer.
- Analysis of existing HDAC inhibitor therapies and their limitations.
- Exploration of the development of isoform-selective HDAC inhibitors.
Main Results:
- HDAC2 overexpression contributes to cancer progression by silencing pro-apoptotic proteins and inactivating tumor suppressors.
- Isoform-selective HDAC inhibition, particularly targeting HDAC2, presents a more effective strategy than pan-HDAC inhibition.
- Development of potent and specific HDAC2 inhibitors requires detailed structural and functional understanding.
Conclusions:
- Targeting HDAC2 specifically is a promising therapeutic strategy for various cancers.
- Further research into HDAC2 structure and function is essential for developing effective selective inhibitors.
- HDAC2 inhibitors could target both direct and indirect pathways crucial for tumor development.
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