Widespread microRNA repression by Myc contributes to tumorigenesis.
The c-Myc oncogenic transcription factor (Myc) is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. Through the analysis of human and mouse models of B cell lymphoma, we show here that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of activation of Myc is widespread repression of miRNA expression. Chromatin immunoprecipitation reveals that much of this repression is likely to be a direct result of Myc binding to miRNA promoters. We further show that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Tsung-Cheng
TC
Chang
Duonan
D
Yu
Yun-Sil
YS
Lee
Erik A
EA
Wentzel
Dan E
DE
Arking
Kristin M
KM
West
Chi V
CV
Dang
Andrei
A
Thomas-Tikhonenko
Joshua T
JT
Mendell
D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc