Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

Dooil Jeoung,Jang-Hee Hahn,Hansoo Lee,Young-Myeong Kim,Hyunmi Park,Jongseon Choe,Deokbum Park,Yun-Sil Lee,Youngmi Kim

doi:10.1074/jbc.m109.095950

Abstract

The role of the cancer/testis antigen CAGE in drug resistance was investigated. The drug-resistant human melanoma Malme3M (Malme3M(R)) and the human hepatic cancer cell line SNU387 (SNU387(R)) showed in vivo drug resistance and CAGE induction. Induction of CAGE resulted from decreased expression and thereby displacement of DNA methyltransferase 1(DNMT1) from CAGE promoter sequences. Various drugs induce expression of CAGE by decreasing expression of DNMT1, and hypomethylation of CAGE was correlated with the increased expression of CAGE. Down-regulation of CAGE in these cell lines decreased invasion and enhanced drug sensitivity resulting from increased apoptosis. Down-regulation of CAGE also led to decreased anchorage-independent growth. Down-regulation of CAGE led to increased expression of p53, suggesting that CAGE may act as a negative regulator of p53. Down-regulation of p53 enhanced resistance to drugs and prevented drugs from exerting apoptotic effects. In SNU387(R) cells, CAGE induced the interaction between histone deacetylase 2 (HDAC2) and Snail, which exerted a negative effect on p53 expression. Chromatin immunoprecipitation assay showed that CAGE, through interaction with HDAC2, exerted a negative effect on p53 expression in Malme3M(R) cells. These results suggest that CAGE confers drug resistance by regulating expression of p53 through HDAC2. Taken together, these results show the potential value of CAGE as a target for the development of cancer therapeutics.

Highlights

Cancer cell lines [1]
We examined the role of CAGE in drug resistance as well as the mechanism of CAGEpromoted drug resistance
Celastrol and taxol deactivity (Fig. 2, C and D). We examined whether these cell crease the expression of DNA Methyltransferase 1 (DNMT1) in both SNU387

Summary

Introduction

Cancer cell lines [1]. CAGE is localized to the X chromosome and exists as single copy [1]. To examine the role of CAGE in drug binding to CAGE promoter sequences is evident in both resistance, we established drug-resistant cancer cell lines by SNU387R and Malme3MR (Fig. 4D). SNU387R and Malme3MR cell lines show enhanced methylation of CAGE promoter sequences (Fig. 4G).

Results

Conclusion