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Breast Cancer Research and Treatment

, Volume 123, Issue 2, pp 359–373 | Cite as

UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer

  • Wei Jin
  • Li Chen
  • Ying Chen
  • Si-guang Xu
  • Gen-hong Di
  • Wen-jin Yin
  • Jiong Wu
  • Zhi-ming Shao
Preclinical study

Abstract

BRCA1 is closely related to the pathogenesis of breast cancer, BRCA1 mRNA is reduced in sporadic breast cancer cells despite the lack of mutations. In the present report, we found that overexpression of UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) was closely related to DNA methylation, deacetylation, and methylation of histones, recruitment of an inhibiting transcriptional complex on the BRCA1 promoter in sporadic breast cancer. Overexpression of UHRF1 induced deacetylation of histones H3 and H4, which was facilitated by recruitment of histone deacetylase1 (HDAC1) to the BRCA1 promoter. Loss of acetylation was accompanied by loss of binding of the key transcription factors MyoD, CBP, and p300. UHRF1 also recruited histone lysine methyltransferase G9a to the BRCA1 promoter and histone 3 lysine 4 (H3K4) was demethylated, and histone 3 lysine 9 (H3K9) was methylated. Finally, overexpression of UHRF1 leaded to methylation of BRCA1 promoter by recruitment of DNMT1 to the BRCA1 promoter, locking in marked suppression of BRCA1. It is the first to describe that UHRF1 is responsible for regulating BRCA1 transcription by inducing DNA methylation, histone modifications, and recruitment of transcriptional complex on the BRCA1 promoter, UHRF1 is a new bio-marker in sporadic breast cancer.

Keywords

UHRF1 BRCA1 promoter DNA methylation Histone modification 

Abbreviation

UHRF1

Ubiquitin-like, containing PHD and RING finger domains 1

E2

17β-Estradiol

HAT

Histone acetyltransferase

DNMT1

DNA methyltransferase 1

HDAC1

Histone deacetylase 1

PBS

Phosphate-buffered saline

FBS

Fetal bovine serum

H3K4

Histone 3 lysine 4

H3K9

Histone 3 lysine 9

H3K4me3

Trimethylation of lysine 4 at H3

H3K9me2

Dimethylation of lysine 9 at H3

Notes

Acknowledgments

The authors thank the studied women for their willingness to cooperate with our study. The work was supported by the grants from Shanghai Pujiang Program (2008); the Natural Science Foundation of Shanghai (No. 09ZR1406900); the National Basic Research Program of China (2006CB910501), National Natural Science Foundation of China (30371580, 30572109); the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry and Innovation Program of Shanghai Municipal Education Commission (No. 09ZZ04).

Supplementary material

10549_2009_652_MOESM1_ESM.pdf (15 kb)
Supplementary material 1 (14 kB)

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  1. 1.Department of Breast Surgery, Breast Cancer Institute, Cancer Hospital/Cancer Institute, Department of Oncology, Shanghai Medical College, Institutes of Biomedical ScienceFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Breast Surgery, Breast Cancer Institute, Cancer Hospital/Cancer InstituteFudan UniversityShanghaiPeople’s Republic of China

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