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Non-canonical roles of PFKFB3 in regulation of cell cycle through binding to CDK4

Oncogenevolume 37pages16851698 (2018) | Download Citation


There is growing interest in studying the molecular mechanisms of crosstalk between cancer metabolism and the cell cycle. 6-phosphate fructose-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a well-known glycolytic activator that plays an important role in tumorigenesis. We investigated whether PFKFB3 was directly involved in oncogenic signaling networks. Mass Spectrometry showed that PFKFB3 interacts with cyclin-dependent kinase (CDK) 4, which controls the transition from G1 phase to S phase of the cell cycle. Further analysis indicated that lysine 147 was a key site for the binding of PFKBFB3 to CDK4. PFKFB3 binding resulted in the accumulation of CDK4 protein by inhibiting ubiquitin proteasome degradation mediated by the heat shock protein 90-Cdc37–CDK4 complex. The proteasome-dependent degradation of CDK4 was accelerated by disrupting the interaction of PFKFB3 with CDK4 by mutating lysine (147) to alanine. Blocking PFKFB3–CDK4 interaction improved the therapeutic effect of FDA-approved CDK4 inhibitor palbociclib on breast cancer. These findings suggest that PFKFB3 is a hub for coordinating cell cycle and glucose metabolism. Combined targeting of PFKFB3 and CDK4 may be new strategy for breast cancer treatment.

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Wenzhi Jia and Xiaoping Zhao authors contributed equally to this work.


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The study was supported by research grants from National Natural Science Foundation of China (No. 81471687, 81530053, 81372195, 81471685, 81572719, 81601520).

Author contributions

JLiu, GH, and ZP designed the project; WJ, LZ, PM, HuY, JLi, and HaY performed the experiments; and WJ., ZP, LZ, PM, HuY, JLi, and HaY analyzed and interpreted the data; L.Z. and PM contributed materials; and JLiu, GH, ZP, and WZ prepared the manuscript.

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    1. Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

      • Wenzhi Jia
      • , Xiaoping Zhao
      • , Li Zhao
      • , Hui Yan
      • , Jiajin Li
      • , Hao Yang
      • , Gang Huang
      •  & Jianjun Liu
    2. Shanghai University of Medicine & Health Sciences, Shanghai, China

      • Gang Huang


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    Correspondence to Gang Huang or Jianjun Liu.

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