Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis

Xiaolong Tang, Guo Li, Lei Shi, Fengting Su, Minxian Qian, Zuojun Liu, Yuan Meng, Shimin Sun, Ji Li and Baohua Liu ()
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Xiaolong Tang: Shenzhen University
Guo Li: Central South University
Lei Shi: Shenzhen University
Fengting Su: Shenzhen University
Minxian Qian: Shenzhen University
Zuojun Liu: Shenzhen University
Yuan Meng: Shenzhen University
Shimin Sun: Shenzhen University
Ji Li: Central South University
Baohua Liu: Shenzhen University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Dietary interventions such as intermittent fasting (IF) have emerged as an attractive strategy for cancer therapies; therefore, understanding the underlying molecular mechanisms is pivotal. Here, we find SIRT7 decline markedly attenuates the anti-tumor effect of IF. Mechanistically, AMP-activated protein kinase (AMPK) phosphorylating SIRT7 at T263 triggers further phosphorylation at T255/S259 by glycogen synthase kinase 3β (GSK3β), which stabilizes SIRT7 by decoupling E3 ligase UBR5. SIRT7 hyperphosphorylation achieves anti-tumor activity by disrupting the SKP2-SCF E3 ligase, thus preventing SKP2-mediated K63-linked AKT polyubiquitination and subsequent activation. In contrast, GSK3β-SIRT7 axis is inhibited by EGF/ERK2 signaling, with ERK2 inactivating GSK3β, thus accelerating SIRT7 degradation. Unfavorably, glucose deprivation or chemotherapy hijacks the GSK3β-SIRT7 axis via ERK2, thus activating AKT and ensuring survival. Notably, Trametinib, an FDA-approved MEK inhibitor, enhances the efficacy of combination therapy with doxorubicin and IF. Overall, we have revealed the GSK3β-SIRT7 axis that must be fine-tuned in the face of the energetic and oncogenic stresses in malignancy.

Date: 2021
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DOI: 10.1038/s41467-021-25274-3

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