Reciprocal Regulation of MicroRNA-122 and c-Myc in Hepatocellular Cancer: Role of E2F1 and Transcription Factor Dimerization Partner 2

• DOI: 10.1002/hep.26712
• Publication Date: 2013-08-28T16:17:41Z
• Authors: Bo Wang; Shu-hao Hsu; Xinmei Wang; Huban Kutay; Hemant Kumar Bid; Jianhua Yu; Ramesh K. Ganju; Samson T. Jacob; Mariia Yuneva; Kalpana Ghoshal
• Keywords: E2F1; Reciprocal; Hepatocellular cancer; MiR-122; Transcription

c-Myc is a well-known oncogene frequently up-regulated in different malignancies, whereas liver-specific microRNA (miR)-122, bona fide tumor suppressor, down-regulated hepatocellular cancer (HCC). Here we explored the underlying mechanism of reciprocal regulation these two genes. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and northern blot analysis demonstrated reduced expression primary, precursor, mature miR-122 c-MYC -induced HCCs compared to benign livers, indicating transcriptional suppression upon MYC overexpression. Indeed, chromatin immunoprecipitation (ChIP) assay showed significantly association RNA II histone H3K9Ac, markers active chromatin, with promoter tumors relative c-MYC-uninduced repression c-MYC-overexpressing tumors. The ChIP also significant increase region that harbors conserved noncanonical binding site livers. Ectopic knockdown studies indeed suppresses primary hepatic cells. Additionally, Hnf-3β, liver enriched transcription factor activates gene, was suppressed c-MYC-induced Notably, repressed by targeting activator E2f1 coactivator Tfdp2, as evident from ectopic luciferase reporter assays mouse human Conclusion : represses gene associating its down-regulating Hnf-3β expression, indirectly inhibits Tfdp2 E2f1. In essence, results suggest double-negative feedback loop between suppressor ( ) an ). (Hepatology 2014;59:555–566)