Widespread microRNA repression by Myc contributes to tumorigenesis

Tsung Cheng Chang; Duonan Yu; Yun Sil Lee; Erik A. Wentzel; Dan E. Arking; Kristin M. West; Chi V. Dang; Andrei Thomas-Tikhonenko; Joshua T. Mendell

doi:10.1038/ng.2007.30

Widespread microRNA repression by Myc contributes to tumorigenesis

Tsung Cheng Chang, Duonan Yu, Yun Sil Lee, Erik A. Wentzel, Dan E. Arking, Kristin M. West, Chi V. Dang, Andrei Thomas-Tikhonenko, Joshua T. Mendell

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1151 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	43-50
Number of pages	8
Journal	Nature genetics
Volume	40
Issue number	1
DOIs	https://doi.org/10.1038/ng.2007.30
State	Published - Jan 2008

ASJC Scopus subject areas

Genetics

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10.1038/ng.2007.30

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title = "Widespread microRNA repression by Myc contributes to tumorigenesis",

abstract = "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.",

author = "Chang, {Tsung Cheng} and Duonan Yu and Lee, {Yun Sil} and Wentzel, {Erik A.} and Arking, {Dan E.} and West, {Kristin M.} and Dang, {Chi V.} and Andrei Thomas-Tikhonenko and Mendell, {Joshua T.}",

note = "Funding Information: We thank D. Eick (GSF Research Centre, Munich) for P493-6 cells; S. Hammond and M. Thomson for assisting with miRNA arrays and for providing Burkitt{\textquoteright}s lymphoma miRNA expression data; and S. McMahon for advice and reagents for Myc knockdown experiments; and K. O{\textquoteright}Donnell and members of the Mendell lab for critical reading of the manuscript. J.T.M. is a Rita Allen Foundation Scholar and receives support from the Lustgarten Foundation for Pancreatic Cancer Research. This work was also supported by grants from the National Institutes of Health (R01CA120185 to J.T.M., and R01CA122334 and R01CA102709 to A.T.-T.).",

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AU - Chang, Tsung Cheng

AU - Yu, Duonan

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AU - West, Kristin M.

AU - Dang, Chi V.

AU - Thomas-Tikhonenko, Andrei

AU - Mendell, Joshua T.

N1 - Funding Information: We thank D. Eick (GSF Research Centre, Munich) for P493-6 cells; S. Hammond and M. Thomson for assisting with miRNA arrays and for providing Burkitt’s lymphoma miRNA expression data; and S. McMahon for advice and reagents for Myc knockdown experiments; and K. O’Donnell and members of the Mendell lab for critical reading of the manuscript. J.T.M. is a Rita Allen Foundation Scholar and receives support from the Lustgarten Foundation for Pancreatic Cancer Research. This work was also supported by grants from the National Institutes of Health (R01CA120185 to J.T.M., and R01CA122334 and R01CA102709 to A.T.-T.).

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N2 - 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.

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Widespread microRNA repression by Myc contributes to tumorigenesis

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