Histone de-acetylase inhibitors: a promising future for cancer treatment?

Raja Samir Khan,Haris Riaz,Ramsha Ali Bhutta,Abdul Nafey Kazi,Harris Hameed

doi:10.1186/1750-9378-8-10

Abstract

Histone de-acetylase proteins or lysine de-acetylases, represent a group of enzymes regulating DNA and gene expression by eliminating acetyl groups (de-acetylation) from lysine amino acids on histones and non-histone proteins. Histone de-acetylase functions normally by being involved in a series of cellular pathways like cell growth, cell cycle, signal transduction, notch signaling pathway and especially transcription.However, abnormal acetylation of histone tails becomes tumorigenic with the resulting transcriptional lesions disrupting the apoptotic program of cells leading to neoplasia. Interaction with the catalytic site and blocking substrate access of histone de-acetylases in proliferation of tumor cells, anti-neoplastic agents called histone de-acetylase inhibitors (HDIs) shift the balance by inducing cell-cycle arrest in G1, activation of differentiation programs and activation of death-receptor and intrinsic apoptotic pathways in neoplastic cells. HDIs anti-proliferative effect in down regulation of BMI1 and c-MYC protein levels has shown promising results in treatment of the incurable AML as well as silencing estrogen receptor alpha in prevention of breast cancer.

Highlights

Histone de-acetylase proteins or lysine de-acetylases, represent a group of enzymes regulating DNA and gene expression by eliminating acetyl groups from lysine amino acids on histones and non-histone proteins [1,2]
histone de-acetylase inhibitors (HDIs) mainly induce activation of both intrinsic and extrinsic apoptotic pathways of neoplastic cells by affecting protein stability, protein-protein interactions through interference with the function of cell cycle proteins such as p21, inhibition of signaling pathways implicated with Raf/MEK and activation of Reactive Oxygen Species [10,11]
Some studies have shown HDIs contributing to growth suppression of primary tumors by enhancing tumor-cell’s immunogenicity via transcriptional activation of MHC (1/2) proteins and suppression of tumor angiogenesis by inhibition of hypoxia-induced VEGF expression [14,15]

Summary

Introduction

Histone de-acetylase proteins or lysine de-acetylases, represent a group of enzymes regulating DNA and gene expression by eliminating acetyl groups (de-acetylation) from lysine amino acids on histones and non-histone proteins [1,2]. HDIs mainly induce activation of both intrinsic and extrinsic apoptotic pathways of neoplastic cells by affecting protein stability, protein-protein interactions through interference with the function of cell cycle proteins such as p21, inhibition of signaling pathways implicated with Raf/MEK and activation of Reactive Oxygen Species [10,11]. HDIs acetylate DNA damage-response proteins, such as Ku70, causing the translocation of BAX to the mitochondria and activating apoptosis [12].

Results

Conclusion