Chromodomain helicase DNA binding protein 5 plays a tumor suppressor role in human breast cancer

Xiao Wu,Jin-Tang Dong,Weidong Li,Dan Su,Xiaodong Sun,Ang Luo,Li Fu,Liya Fu,Zhiqian Zhang,Xiaoying Fu,Zhengmao Zhu

doi:10.1186/bcr3182

Abstract

IntroductionThe chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a tumor suppressor in a mouse model. The CHD5 locus at 1p36 is deleted, and its mutation has been detected in breast cancer. We, therefore, evaluated whether CHD5 plays a role in human breast cancer.MethodsWe screened mutations in 55 tumors, determined promoter methylation in 39 tumors, measured RNA expression in 90 tumors, analyzed protein expression in 289 tumors, and correlated expression changes with clinicopathological characteristics of breast cancer. Functional effects of CHD5 on cell proliferation, invasion and tumorigenesis were also tested.ResultsAlthough only one mutation was detected, CHD5 mRNA expression was significantly reduced, accompanied by frequent genomic deletion and promoter methylation, in breast cancer. The extent of methylation was significantly associated with reduced mRNA expression, and demethylating treatment restored CHD5 expression. Lower CHD5 mRNA levels correlated with lymph node metastasis (P = 0.026). CHD5 protein expression was also reduced in breast cancer, and lack of CHD5 expression significantly correlated with higher tumor stage, ER/PR-negativity, HER2 positivity, distant metastasis and worse patient survival (P ≤ 0.01). Functionally, ectopic expression of CHD5 in breast cancer cells inhibited cell proliferation and invasion in vitro and tumorigenesis in nude mice. Consistent with the inhibition of invasion, CHD5 down-regulated mesenchymal markers vimentin, N-cadherin and ZEB1 in breast cancer cells.ConclusionDown-regulation of CHD5, mediated at least in part by promoter methylation, contributes to the development and progression of human breast cancer.

Highlights

The chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a tumor suppressor in a mouse model
By analyzing mouse models generated by chromosome engineering to obtain different dosages of genomic interval D4Mit190-51, which corresponds to human 1p36, Bagchi et al demonstrated that CHD5 was the leading tumor suppressor gene in this interval [2]
Taken together with previous findings that showed deletion of 1p36 in breast tumors [19,20], our results suggest that CHD5 is a tumor suppressor gene whose inactivation by mutation, chromosomal deletion or promoter methylation-mediated transcriptional down-regulation plays a role in the development and progression of breast cancer

Summary

Introduction

The chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a tumor suppressor in a mouse model. The CHD5 locus at 1p36 is deleted, and its mutation has been detected in breast cancer. We evaluated whether CHD5 plays a role in human breast cancer. Chromosomal loss, which leads to the inactivation of tumor suppressor genes, is one of the most common genetic alterations detected in human cancer. Evidence that CHD5 functions as a tumor suppressor in human cancer has principally come from studies of neuroblastoma, in which CHD5 mRNA expression was down-regulated likely through promoter methylation in tumors, and high expression of CHD5 was statistically associated with better patient survival [7]. Whereas 1p36 is commonly deleted in human breast cancers, the role of CHD5 in breast cancer has not been evaluated

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