2. Academic Validation
  3. Combined intermittent fasting and ERK inhibition enhance the anti-tumor effects of chemotherapy via the GSK3β-SIRT7 axis

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

  • Nat Commun. 2021 Aug 25;12(1):5058. doi: 10.1038/s41467-021-25274-3.
Xiaolong Tang 1 2,  Guo Li 3,  Lei Shi 2,  Fengting Su 1,  Minxian Qian 1 2,  Zuojun Liu 1 2,  Yuan Meng 1,  Shimin Sun 1,  Ji Li 3,  Baohua Liu 4 5 6
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences, Shenzhen University, Shenzhen, China.
  • 2 Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, Shenzhen University, Shenzhen, China.
  • 3 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
  • 4 Shenzhen Key Laboratory of Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences, Shenzhen University, Shenzhen, China. ppliew@szu.edu.cn.
  • 5 Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, Shenzhen University, Shenzhen, China. ppliew@szu.edu.cn.
  • 6 Shenzhen Bay Laboratory, Shenzhen, China. ppliew@szu.edu.cn.
PMID: 34433808 DOI: 10.1038/s41467-021-25274-3
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.

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