Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70.

Ping Gong,Yuetong Wang,Yongkui Jing

doi:10.3390/ijms20071601

Ping Gong, Yuetong Wang + Show 1 more

Open Access

https://doi.org/10.3390/ijms20071601

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Abstract

Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. Treatment with HDAC inhibitors regulates gene expression with increased acetylated histones with unconfirmed connection with therapy. Apoptosis is a key mechanism by which HDAC inhibitors selectively kill cancer cells, probably due to acetylation of non-histone proteins. Ku70 is a protein that repairs DNA breaks and stabilizes anti-apoptotic protein c-FLIP and proapoptotic protein Bax, which is regulated by acetylation. HDAC inhibitors induce Ku70 acetylation with repressed c-FLIP and activated Bax in cancer cells. Current studies indicate that Ku70 is a potential target of HDAC inhibitors and plays an important role during the induction of apoptosis.

Highlights

Aberrant acetylation of histone and/or expression of histone deacetylases (HDACs) exist in various solid and hematologic malignancies and contribute to tumorigenesis [1]
Other research groups and we have found that HDAC inhibitor (HDACi) Trichostatin A, SAHA, Nicotinamide, and Tubacin increase acetylation of Ku70 during the apoptosis induction process [16,62,63,110,111]
A series of HDAC inhibitors have been on the market and in clinical development, the death mechanism caused by HDACis is not fully understood

Summary

Introduction

Aberrant acetylation of histone and/or expression of histone deacetylases (HDACs) exist in various solid and hematologic malignancies and contribute to tumorigenesis [1]. Overexpression of individual HDACs accelerates the proliferation of tumor cells and predicts poor prognosis in many types of cancer patients [2,3,4,5,6,7,8]. Genetic knockdown of an individual HDAC, most notably HDAC1, 2, 3, and 6, in different types of tumor cells, such as Hodgkin’s lymphoma, gastric cancer, prostate cancer, colorectal cancer, pancreatic cancer, and ovarian cancer, induced DNA damage, cell cycle arrest, and/or apoptosis [9]. HDACs are being considered as therapeutic targets for cancer treatment. Increased histone acetylation by HDACi treatment has been observed, this phenomenon could not be linked to therapeutic outcome. HDACis induce apoptosis in many types of cancer cells and show relative selectivity to malignant cells. The development of HDACis and the potential roles of Ku70 in the HDACi-induced apoptosis are summarized

Classification of HDACs and Cellular Location

HDACi for Cancer Therapy

Apoptosis Induction by HDACis

Ku70 Regulates Apoptosis-Related Proteins

Ku70 Acetylation by HDACi Treatment

Summary