UHRF1 Modulate Transcriptional Activity Of The BRCA1 Gene In Sporadic Breast Cancer

UHRF1 modulate transcriptional activity of the BRCA1 gene in sporadic breast cancerObjective:To investigate how UHRF1 regulates BRCA1 transcription in sporadic breast cancer.Methods:We transiently transfected UHRF1 plasmids into breast cancer cell lines, then performed RT-PCR,Western—blot, CHIP to detect whether they could combine to the BRCA1 promoter, regulate its transcription and affect its protein level.Results:UHRF1 is associated with BRCA1 expression in BRCA1 methylated breast tumors and normal breast tissues. ChIP results demonstrated that MyoD, CBP/p300 could bind directly to the BRCAl promoter in normal breast tissues and UHRFl, HDAC1, DNMT1, or G9a could bind directly to the BRCA1 promoter in BRCA1 methylated tumors. ChIP-reChIP results indicated that UHRF1 and HDAC1, DNMT1, G9a formed an inhibiting transcriptional complex on the BRCA1 promoter in BRCA1 methylated breast tumors. Luciferase activity indicated that UHRF1 complex were involved in the inhibition of the BRCA1 promoter. UHRF1 siRNA activated BRCA1 expression significantly. UHRF1 siRNA attenuated the UHRF1 complex to the BRCA1 promoter. E2 stimulated BRCA1 promoter activity. ChIP experiments showed that E2 repressed the recruitment of UHRF1 complex to the BRCA1 promoter. Overexpression of UHRF1 attenuates BRCA1 expression and reverses the epigenetic characteristics of the BRCA1 promoter induced by E2. UHRF1 represses the ability of BRCA1 to protect cells against H2O2.Conclusion:overexpression of UHRF1 is closely related to DNA methylation, deacetylation, and methylation of histones, recruitment of an inhibiting transcriptional complex on the BRCA1 promoter in sporadic breast cancer. UHRF1 is a new oncogene related to sporadic breast cancer.