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

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.