MYC Protein Inhibits Transcription of the MicroRNA Cluster MC-let-7a-1 similar to let-7d via Noncanonical E-box
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AbstractThe human microRNA cluster MC-let-7a-1 similar to let-7d, with three members let-7a-1, let-7f-1, and let-7d, is an important cluster of the let-7 family. These microRNAs play critical roles in regulating development and carcinogenesis. Therefore, precise control of MC-let-7a-1 similar to let-7d level is critical for cellular functions. In this study, we first showed that the expression of these three members was significantly reduced in human hepatocellular carcinoma HepG2 cells as compared with the immortalized human liver L02 cells. We demonstrated that the MC-let-7a-1 similar to let-7d cluster was encoded by a single polycistronic transcript driven by a 10-kb upstream promoter, with two MYC-binding sites. Importantly, MYC inhibited MC-let-7a-1 similar to let-7d promoter activity via binding to the noncanonical E-box 3 downstream of the transcription start sites, whereas it enhanced promoter activity by binding to the canonical E-box 2 upstream of the transcription start sites. We found that although the binding affinity of MYC to E-box 2 was stronger than E-box 3, the binding quantum of MYC to E-box 3 was significantly higher in cancerous HepG2 cells as compared with the noncancerous L02 cells. In addition, forced expression of let-7 could reverse the MYC-mediated cell proliferation. These findings suggested that in L02 cells with a low level of MYC, MYC binds mainly to E-box 2 to enhance MC-let-7a-1 similar to let-7d expression. However, in HepG2 cells with an elevated MYC, the extra MYC could bind to E-box 3 to suppress the transcription of MC-let-7a-1 similar to let-7d and thus enable HepG2 cells to maintain a high level of MYC and a low level of let-7 microRNAs simultaneously.
All Author(s) ListWang ZF, Lin S, Li JLJ, Xu ZH, Yao H, Zhu X, Xie D, Shen Z, Sze J, Li K, Lu G, Chan DTM, Poon WS, Kung HF, Lin MCM
Journal nameJournal of Biological Chemistry
Volume Number286
Issue Number46
PublisherAmerican Society for Biochemistry and Molecular Biology
Pages39703 - 39714
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesBiochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY

Last updated on 2021-07-01 at 23:53