title: SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status.
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.affiliation: Department of Radiation Oncology, Laboratory for Molecular Cancer Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Ha Yong
authors.initials: HY
authors.lastname: Song
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Biancucci
authors.affiliation: Department of Radiation Oncology, Laboratory for Molecular Cancer Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Radiation Oncology, Laboratory for Molecular Cancer Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: O'Callaghan
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, Laboratory for Molecular Cancer Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Yufan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Karla Fullner
authors.initials: KF
authors.lastname: Satchell
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Kirtee
authors.initials: K
authors.lastname: Raparia
authors.affiliation: Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.affiliation: Department of Radiation Oncology, Laboratory for Molecular Cancer Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
mesh_terms: D000107:Acetylation; D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008239:Lysine; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056565:Sirtuin 2 / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D047368:Tumor Burden
chemical_list: C418743:Sirt2 protein, mouse; D056565:Sirtuin 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D008239:Lysine
keywords: KRAS; SIRT2; acetylation; lung cancer; pancreas transformation