Oncotarget

Research Papers:

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 and Athanassios Vassilopoulos _

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Oncotarget. 2016; 7:80336-80349. https://doi.org/10.18632/oncotarget.12015

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Abstract

Ha Yong Song1, Marco Biancucci2, Hong-Jun Kang1, Carol O’Callaghan1, Seong-Hoon Park3, Daniel R. Principe3, Haiyan Jiang3, Yufan Yan1, Karla Fullner Satchell2, Kirtee Raparia4, David Gius3 and Athanassios Vassilopoulos1

1 Department of Radiation Oncology, Laboratory for Molecular Cancer Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

2 Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

3 Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

4 Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

Correspondence to:

Athanassios Vassilopoulos, email:

David Gius, email:

Keywords: KRAS, SIRT2, acetylation, lung cancer, pancreas transformation

Received: August 23, 2016 Accepted: September 02, 2016 Published: September 13, 2016

Abstract

The observation that cellular transformation depends on breaching a crucial KRAS activity threshold, along with the finding that only a small percentage of cellsharboring 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.


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