Enhanced Deacetylation of p53 by the Anti-apoptotic Protein HSCO in Association with Histone Deacetylase 1

Hisako Higashitsuji,Hiroaki Higashitsuji,Tomoko Masuda,Yu Liu,Katsuhiko Itoh,Jun Fujita

doi:10.1074/jbc.m609751200

Hisako Higashitsuji, Hiroaki Higashitsuji + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m609751200

Copy DOI

Journal: Journal of Biological Chemistry	Publication Date: May 1, 2007
Citations: 43	License type: cc-by

Affiliation: Kyoto University

Abstract

HSCO (hepatoma subtracted-cDNA library clone one, also called ETHE1) was originally identified by its frequent overexpression in hepatocellular carcinomas. HSCO inhibits function of NF-kappaB by binding to RelA and accelerating its export from the nucleus. We show here that HSCO exhibits anti-apoptotic activity in cells exposed to DNA-damaging agents by suppressing transcriptional activity of p53. Induction of pro-apoptotic genes, Noxa, Perp, PIG3, and Bax were suppressed in cells over-expressing HSCO. By increasing ubiquitylation and degradation of p53, HSCO reduces p53 protein levels. HSCO specifically associates with histone deacetylase 1 (HDAC1) independently of Mdm2 and facilitates deacetylation of p53 at Lys-373/382 by HDAC1. The metallo-beta-lactamase family consensus sequence in HSCO is important for its effect on p53 deacetylation. Co-immunoprecipitation and immunofluorescence studies suggested that HSCO, HDAC1, and p53 form a complex in the nucleus. Thus, HSCO is a cofactor that increases the deacetylase activity of HDAC1 toward p53, leading to suppression of apoptosis. Treatment of hepatocellular carcinomas that retain wild-type p53 and overexpress HSCO with anti-HSCO agents might re-establish the p53 response and revert chemoresistance.

Highlights

13716 JOURNAL OF BIOLOGICAL CHEMISTRY functions as a sequence-specific DNA-binding transcription factor to activate or repress a large number of target genes, which mediate cell-cycle arrest, apoptosis, senescence, differentiation, DNA repair, and inhibition of angiogenesis and metastasis [6]
Histone deacetylase (HDAC)-1, -2, and -3 are all capable of down-regulating p53 transcriptional activity, which is dependent on the deacetylase activity of HDACs and p53 acetylation mediated by p300/CBP [13]
Because reduction of p53 acetylation by HSCO was sensitive to trichostatin A (TSA) inhibition, but not to nicotinamide, HDAC(s) of Class I and/or II must be involved

Summary

Introduction

13716 JOURNAL OF BIOLOGICAL CHEMISTRY functions as a sequence-specific DNA-binding transcription factor to activate or repress a large number of target genes, which mediate cell-cycle arrest, apoptosis, senescence, differentiation, DNA repair, and inhibition of angiogenesis and metastasis [6]. In Vivo p53 Acetylation and Deacetylation Assays—For in vivo p53 acetylation assays, 293T cells were transfected with plasmids expressing wild-type or mutant (H79N or R159H) HSCO, Mdm2, and p300. For in vivo p53 deacetylation assays, p53-null H1299 cells were co-transfected with plasmids expressing p53, wild-type or mutant (H141A) HDAC1, HSCO, and p300.

Results

Conclusion