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

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

doi:10.18632/oncotarget.12015

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.

Highlights

Sirtuin genes are the human and murine homologs of the S. cerevisiae Sir2 gene that have been shown to regulate both replicative and overall lifespan [1]
Sirt2-/-KrasG12D-Ptf1 mice showed an increase in induction and pancreatic intraepithelial neoplasia (PanIN) progression compared to KrasG12D-Ptf1 mice as revealed by the amount and grade of these lesions both at 4 and 6 months of age (Figure 1C)
Regarding SIRT2, we have previously shown that Sirt2-deficient mice develop tumors in several tissues, providing the first strong genetic evidence that SIRT2 may function as a tumor suppressor through its role in regulating the anaphase-promoting complex/cyclosome (APC/C) [5]

Summary

Introduction

Sirtuin genes are the human and murine homologs of the S. cerevisiae Sir gene that have been shown to regulate both replicative and overall lifespan [1]. Despite the observed discrepancies and the scarcity of detailed mechanisms regarding the role of sirtuins in longevity, it is well established that they do appear to direct critical acetylome signaling networks responding to caloric restriction (CR) [3], and following stress, several mice lacking one of the sirtuin genes develop illnesses that mimic those observed in humans that are strongly connected to increasing age [4]. Consistent with this, mice lacking Sirt2 [5] develop multiple epithelial malignancies, including pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LACA). Based on these findings, it has been suggested that sirtuins are energy/nutrient stress sensor proteins that alter the activity of downstream signaling networks and targets via post-translational modifications (PTMs) involving lysine deacetylation in response to specific types of cellular stress. Identification of mechanisms which may contribute to breaching a crucial enzymatic KRAS activity threshold to initiate carcinogenesis, even in the presence of activating KRAS mutations, may fill the critical gap in knowledge related to KRAS-driven tumorigenesis

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