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.
|
Authors | 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 |
Journal | Oncotarget
(Oncotarget)
Vol. 7
Issue 49
Pg. 80336-80349
(Dec 06 2016)
ISSN: 1949-2553 [Electronic] United States |
PMID | 27637077
(Publication Type: Journal Article)
|
Chemical References |
- Sirt2 protein, mouse
- Sirtuin 2
- Hras protein, mouse
- Proto-Oncogene Proteins p21(ras)
- Lysine
|
Topics |
- Acetylation
- Adenocarcinoma
(enzymology, genetics, pathology)
- Adenocarcinoma of Lung
- Animals
- Cell Proliferation
- Cell Transformation, Neoplastic
(genetics, metabolism, pathology)
- Gene Deletion
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- HCT116 Cells
- HEK293 Cells
- Humans
- Lung Neoplasms
(enzymology, genetics, pathology)
- Lysine
- Male
- Mice
- Mice, Knockout
- Mice, Nude
- Mutation
- NIH 3T3 Cells
- Pancreatic Neoplasms
(enzymology, genetics, pathology)
- Phenotype
- Protein Processing, Post-Translational
- Proto-Oncogene Proteins p21(ras)
(genetics, metabolism)
- Signal Transduction
- Sirtuin 2
(deficiency, genetics)
- Time Factors
- Tumor Burden
|