Research Papers:

Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth

Ye Xiangyun, Niu Xiaomin, Gu linping, Xu Yunhua, Li Ziming, Yu Yongfeng, Chen Zhiwei _ and Lu Shun

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Oncotarget. 2017; 8:6984-6993. https://doi.org/10.18632/oncotarget.14346

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Ye Xiangyun1,*, Niu Xiaomin1,*, Gu linping1, Xu Yunhua1, Li Ziming1, Yu Yongfeng1, Chen Zhiwei1, Lu Shun1

1Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China

*These authors should be regarded as joint first authors

Correspondence to:

Chen Zhiwei, email: [email protected]

Lu Shun, email: [email protected]

Keywords: PKM2, succinylation, SIRT5, ROS, tumor growth

Received: February 02, 2016    Accepted: December 05, 2016    Published: December 28, 2016


Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research.

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