Chromatin Remodeling, Cancer and Chemotherapy

Abstract

DNA in eukaryotic nucleus is highly condensed with histone proteins as nucleosomes. Three dimensional arrangements of nucleosomes give rise to the formation of chromatin. Extensive studies in the recent years have highlighted that the structure of chromatin plays a critical role in gene expression. Post translational modifications (such as acetylation, deacetylation, methylation and phosphorylation etc.) of tails of histones may occur with the help of various histone modifier proteins which may lead to architectural changes of nucleosomes and chromatin remodeling. Chromatin remodeling may finally enhance or repress gene transcriptions. The neoplastic cells selectively take the advantages of histone modifications for the cell proliferation, differentiation and evasion of apoptosis. There are enough experimental and clinical evidences that various histone modifiers are linked with many human malignancies. The thorough knowledge of manipulation of histone modifiers by cancer cells may help us to design newer anti-neoplastic drugs in future. There is considerable interest in histone deactylase inhibitors as antineoplastic agents and various clinical trials are in progress. This article reviews a general overview of chromatin remodeling proteins, their role in carcinogenesis and the future potential of the histone deacetylase inhibitors in cancer chemotherapy.

Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer

“…This finding was consistent with those of previous studies showing that HDAC inhibitors usually produce cytotoxicity and induce G 1 arrest at lower concentrations [ 21 , 22 ]. The major molecular effect of HDAC inhibition is to change the acetylation status of core histone proteins, consequently facilitating chromatin remodeling and thus altering gene expression and cell differentiation [ 26 – 28 ]. Consistent with this, we found that HNHA upregulated p21 expression and downregulated cyclin D1 in the ATC and PTC cell lines.…”

Investigating the Selectivity of Metalloenzyme Inhibitors

“…Inhibitors of HDACs, such as suberoylanilide hydroxamic acid (SAHA, vorinostat, Merck), activate tumor suppression genes within cancerous cells leading to growth arrest and cell death. 46 SAHA, a first-in-class, broad spectrum HDAC inhibitor, is a relatively simple molecule incorporating a hydroxamic acid MBG, an aliphatic linker, and an aromatic capping group (Figure 1). SAHA was discovered in 1996 by Richon et al 25 and approved by the FDA as a treatment for cutaneous T-cell lymphoma in 2006.…”

Decoding the Tumour Microenvironment: Molecular Players, Pathways, and Therapeutic Targets in Cancer Treatment

“…Epigenetics is essential in several mechanisms and comprises changes in the gene expression that do not involve alterations in the DNA sequence; instead, it involves all the modifications that alter the chromatin packing [26]. Hence, these changes are more flexible and versatile, and can also propagate in various cell cycles [27]. Epigenetic programming is critical for the development and maintenance of tissue-and cell-type-specific functions [28].…”