Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation

Tsung Cheng Chang, Lauren R. Zeitels, Hun Way Hwang, Raghu R. Chivukula, Erik A. Wentzel, Michael Dews, Jason Jung, Ping Gao, Chi V. Dang, Michael A. Beer, Andrei Thomas-Tikhonenko, Joshua T. Mendella

Research output: Contribution to journalArticlepeer-review

298 Scopus citations

Abstract

Direct control of microRNA (miRNA) expression by oncogenic and tumor suppressor networks results in frequent dysregulation of miRNAs in cancer cells and contributes to tumorigenesis. We previously demonstrated that activation of the c-Myc oncogenic transcription factor (Myc) broadly influences miRNA expression and in particular leads to widespread miRNA down-regulation. miRNA transcripts repressed by Myc include several with potent tumor suppressor activity such as miR-15a/16-1, miR-34a, and let-7 family members. In this study, we have investigated mechanisms downstream of Myc that contribute to miRNA repression. Consistent with transcriptional down-regulation, Myc activity results in the decreased abundance of multiple miRNA primary transcripts. Surprisingly, however, primary transcripts encoding several let-7 miRNAs are not reduced in the high Myc state, suggesting a posttranscriptional mechanism of repression. The Lin-28 and Lin-28B RNA binding proteins were recently demonstrated to negatively regulate let-7 biogenesis. We now show that Myc induces Lin-28B expression in multiple human and mouse tumor models. Chromatin immunoprecipitation and reporter assays reveal direct association of Myc with the Lin-28B promoter resulting in transcriptional transactivation. Moreover, we document that activation of Lin-28B is necessary and sufficient for Myc-mediated let-7 repression. Accordingly, Lin-28B loss-of-function significantly impairs Myc-dependent cellular proliferation. These findings highlight an important role for Lin-28B in Myc-driven cellular phenotypes and uncover an orchestration of transcriptional and posttranscriptional mechanisms in Myc-mediated reprogramming of miRNA expression.

Original languageEnglish (US)
Pages (from-to)3384-3389
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number9
DOIs
StatePublished - Mar 3 2009

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation'. Together they form a unique fingerprint.

Cite this