A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

Kathryn A O'Donnell-Mendell, Vincent W. Keng, Brian York, Erin L. Reineke, Daekwan Seo, Danhua Fan, Kevin A T Silverstein, Christina T. Schrum, Wei Rose Xie, Loris Mularoni, Sarah J. Wheelan, Michael S. Torbenson, Bert W. O'Malley, David A. Largaespada, Jef D. Boeke

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy.

Original languageEnglish (US)
Pages (from-to)E1377-E1386
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number21
DOIs
StatePublished - May 22 2012

Keywords

  • Cancer gene identification
  • Hepatocellular carcinoma
  • Mouse models of cancer
  • Myc oncogene

ASJC Scopus subject areas

  • General

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    O'Donnell-Mendell, K. A., Keng, V. W., York, B., Reineke, E. L., Seo, D., Fan, D., Silverstein, K. A. T., Schrum, C. T., Xie, W. R., Mularoni, L., Wheelan, S. J., Torbenson, M. S., O'Malley, B. W., Largaespada, D. A., & Boeke, J. D. (2012). A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer. Proceedings of the National Academy of Sciences of the United States of America, 109(21), E1377-E1386. https://doi.org/10.1073/pnas.1115433109