UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer.
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.
Jin
Wei
W
Department of Breast Surgery, Breast Cancer Institute, Cancer Hospital/Cancer Institute, Fudan University, 200032, Shanghai, People's Republic of China. jinwei7207@163.com
Chen
Li
L
Chen
Ying
Y
Xu
Si-Guang
SG
Di
Gen-Hong
GH
Yin
Wen-Jin
WJ
Wu
Jiong
J
Shao
Zhi-Ming
ZM
D000107:Acetylation; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D050881:E1A-Associated p300 Protein / Q000235:genetics; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006649:Histocompatibility Antigens / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007150:Immunohistochemistry; D008745:Methylation; D017570:MyoD Protein / Q000235:genetics; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D006649:Histocompatibility Antigens; D006657:Histones; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D016877:Oxidants; D004958:Estradiol; D006861:Hydrogen Peroxide; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1