Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis

Fu-Long Li, Jin-Ping Liu, Ruo-Xuan Bao, GuoQuan Yan, Xu Feng, Yan-Ping Xu, Yi-Ping Sun, Weili Yan, Zhi-Qiang Ling, Yue Xiong, Kun-Liang Guan and Hai-Xin Yuan ()
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Fu-Long Li: Fudan University
Jin-Ping Liu: Fudan University
Ruo-Xuan Bao: Fudan University
GuoQuan Yan: Fudan University
Xu Feng: Fudan University
Yan-Ping Xu: University of North Carolina at Chapel Hill
Yi-Ping Sun: Fudan University
Weili Yan: Children’s Hospital of Fudan University
Zhi-Qiang Ling: Zhejiang Province Cancer Hospital Zhejiang Cancer Center
Yue Xiong: Fudan University
Kun-Liang Guan: Fudan University
Hai-Xin Yuan: Fudan University

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.

Date: 2018
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DOI: 10.1038/s41467-018-02950-5

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