The application of histone deacetylases inhibitors in glioblastoma

Abstract

The epigenetic abnormality is generally accepted as the key to cancer initiation. Epigenetics that ensure the somatic inheritance of differentiated state is defined as a crucial factor influencing malignant phenotype without altering genotype. Histone modification is one such alteration playing an essential role in tumor formation, progression, and resistance to treatment. Notably, changes in histone acetylation have been strongly linked to gene expression, cell cycle, and carcinogenesis. The balance of two types of enzyme, histone acetyltransferases (HATs) and histone deacetylases (HDACs), determines the stage of histone acetylation and then the architecture of chromatin. Changes in chromatin structure result in transcriptional dysregulation of genes that are involved in cell-cycle progression, differentiation, apoptosis, and so on. Recently, HDAC inhibitors (HDACis) are identified as novel agents to keep this balance, leading to numerous researches on it for more effective strategies against cancers, including glioblastoma (GBM). This review elaborated influences on gene expression and tumorigenesis by acetylation and the antitumor mechanism of HDACis. Besdes, we outlined the preclinical and clinical advancement of HDACis in GBM as monotherapies and combination therapies.

Keywords: epigenetic; gene expression; glioblastoma; histone acetylation, histone deacetylation; histone deacetylases inhibitors.

Figure 1

Regulation of chromatin remodeling and gene expression by acetylation. Acetylation(Ac) of the histone tills is the foundation of transcription activation. Acetyl groups on Lys residues transferred by HATs neutralizes the positively charged protruding tails, preventing the interactions with negatively charged one and thus presenting chromatin decondensation. Later this open state allows access to transcription factors and other transcription co-activators termed ‘readers’ by their contained bromodomain recognizing acetylation site on histone tails