Snail Regulates Hepatocellular Carcinoma Orphan Nuclear Receptor Nur77 Promoter Methylation

Nur77 is a member of the steroid/thyoid/retinoid nuclear receptor superfamily.Although it plays an important role in cell proliferation,apoptosis,development of colon cancer and melanoma,there is less study focused on Nur77 and hepatocarcinoma.Based on the Oncomine Database information,we found that the expression of Nur77 in para-carcinoma is higher than that in paired carcinoma in clinical samples,Using ADC,the inhibitor of DNA methyltransferase,to treat liver cancer cells,we found a DNA methylation occurred in the Nur77 promoter.By means of sequence alignment,there are five E-boxes(CAGGTG)in the Nur77 promoter,which is responsible for the transcriptional repressor Snail specific binding to Nur77 promoter.Upon overexpression or knockdown of Snail in lever cancer cells,Nur77 was negatively regulated by Snail in mRNA level,protein level and its promoter activity.With a series of ChIP assays,we proved that the Nur77 promoter is combined with chromosome remodelers HDAC1,HDAC2 and DNA methyltransferase,which results in Nur77 promoter acetylation and DNA methylation,thereby decreasing the transcription activity of Nur77,finally inhibiting expression of Nur77 in liver cancer.In summary,our study clarifies that the transcription repressior Snail can affect Nur77 expression by regulating Nur77 promoter.Snail binds to Nur77 promoter E-box,then recruits chromosome remodelers and DNA methyltransferase to the Nur77 promoter,thereby leading to Nur77 promoter deacetylation in H3K9 and DNA methylation,finally repressing the expression of Nur77.Therefore,Nur77 may be a novel target for liver cancer detection and treatment in clinical,and our study further provides a new strategy to detection and treatment of HCC.