Characterization of the HDAC1 Complex That Regulates the Sensitivity of Cancer Cells to Oxidative Stress

Takuya Kato,Yoshiki Murakumo,Yohei Shimono,Atsushi Enomoto,Naoya Asai,Mayumi Jijiwa,Masahide Takahashi,Masaki Hasegawa

doi:10.1158/0008-5472.can-08-4368

Takuya Kato, Yoshiki Murakumo + Show 6 more

Open Access

https://doi.org/10.1158/0008-5472.can-08-4368

Copy DOI

Journal: Cancer Research	Publication Date: Apr 15, 2009
Citations: 62	License type: cc-by

Affiliation: Nagoya University, Nagoya Medical Center

Abstract

Histone deacetylases (HDAC) are involved in carcinogenesis through their regulation of cell proliferation, differentiation, and survival. The inhibitors of HDAC exhibit profound synergistic effects in cancer treatment when combined with other anticancer drugs. However, the molecular mechanisms underlying this synergy are not fully understood. Here, we show that HDAC1 increases the resistance of cancer cells to oxidative stress by negatively regulating the expression of thioredoxin binding protein 2 (TBP-2). We found that the recruitment of HDAC1 to the TBP-2 promoter is mediated by a protein complex consisting of RET finger protein (RFP; also called TRIM27) and the trimeric transcription factor NF-Y. Accordingly, RNA interference-mediated depletion of RFP led to the disruption of the protein complex and a marked increase in the sensitivity of cancer cells to cisplatin, a potent inducer of oxidative stress. Furthermore, high levels of RFP expression correlated with down-regulation of TBP-2 in human colon cancers and were associated with poor clinical outcome. These findings reveal the diverse cancer-promoting activities of HDAC1 and identify RFP as a key regulator that provides cancer cells with resistance to anticancer drugs.

Highlights

The acetylation and deacetylation of lysines in the NH2terminal tails of core histones play crucial roles in the remodeling of chromatin and regulation of transcription
To investigate the molecular mechanism underlying sensitization of cancer cells to oxidative stress, we focused on the roles of HDAC1, which is a well-studied member of Histone deacetylases (HDAC)
It has been proposed that p53 associates with HDAC1 and thereby regulates cellular sensitivity to oxidative stress [21, 34,35,36], other mechanisms may be important in HeLa cells because p53 is inactivated by the papillomavirus protein E6 in these cells

Summary

Introduction

The acetylation and deacetylation of lysines in the NH2terminal tails of core histones play crucial roles in the remodeling of chromatin and regulation of transcription. Histone deacetylases (HDAC) catalyze the removal of acetyl moieties from histones that cause chromatin compaction and preclude access by the transcriptional machinery, resulting in transcriptional repression. HDACs target many other protein substrates and affect their functions in cell proliferation and cell death [1, 2]. Mammalian HDACs are divided into several classes based on their sequence similarity to yeast prototypes. Class I HDACs (HDAC1, HDAC2, HDAC3, and HDAC8) are primarily nuclear in localization and ubiquitously expressed and act on. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

Methods

Results

Conclusion