SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status

Ha Yong Song, Marco Biancucci, Hong Jun Kang, Carol O'Callaghan, Seong Hoon Park, Daniel R. Principe, Haiyan Jiang, Yufan Yan, Karla Fullner Satchell, Kirtee Raparia, David Gius*, Athanassios Vassilopoulos

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The observation that cellular transformation depends on breaching a crucial KRAS activity threshold, along with the finding that only a small percentage of cells harboring KRAS mutations are transformed, support the idea that additional, not fully uncovered, regulatory mechanisms may contribute to KRAS activation. Here we report that KrasG12D mice lacking Sirt2 show an aggressive tumorigenic phenotype as compared to KrasG12D mice. This phenotype includes increased proliferation, KRAS acetylation, and activation of RAS downstream signaling markers. Mechanistically, KRAS K147 is identified as a novel SIRT2-specific deacetylation target by mass spectrometry, whereas its acetylation status directly regulates KRAS activity, ultimately exerting an impact on cellular behavior as revealed by cell proliferation, colony formation, and tumor growth. Given the significance of KRAS activity as a driver in tumorigenesis, identification of K147 acetylation as a novel post-translational modification directed by SIRT2 in vivo may provide a better understanding of the mechanistic link regarding the crosstalk between non-genetic and genetic factors in KRAS driven tumors.

Original languageEnglish (US)
Pages (from-to)80336-80349
Number of pages14
JournalOncotarget
Volume7
Issue number49
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Acetylation
  • KRAS
  • Lung cancer
  • Pancreas transformation
  • SIRT2

ASJC Scopus subject areas

  • Oncology

Cite this

Song, H. Y., Biancucci, M., Kang, H. J., O'Callaghan, C., Park, S. H., Principe, D. R., Jiang, H., Yan, Y., Satchell, K. F., Raparia, K., Gius, D., & Vassilopoulos, A. (2016). SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status. Oncotarget, 7(49), 80336-80349. https://doi.org/10.18632/oncotarget.12015