The histone deacetylase SIRT6 promotes glycolysis through the HIF-1α/HK2 signaling axis and induces erlotinib resistance in non-small cell lung cancer

• Published in: Apoptosis (London) 2022-12, Vol.27 (11-12), p.883-898
• Main Authors: You, Qiai, Wang, Jianmin, Yu, Yongxin, Li, Feng, Meng, Lingxin, Chen, Mingjing, Yang, Qiao, Xu, Zihan, Sun, Jianguo, Zhuo, Wenlei, Chen, Zhengtang
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Anticancer properties; Antitumor activity; Apoptosis; Biochemistry; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Drug resistance; Energy metabolism; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; Glycolysis; Growth factors; Histone deacetylase; Histones; Hypoxia-inducible factor 1a; Kinases; Lung cancer; Medical prognosis; Metabolic pathways; Mutation; Non-small cell lung carcinoma; Oncology; Patients; Protein-tyrosine kinase receptors; Sensitivity; Signaling; Small cell lung carcinoma; Targeted cancer therapy; Therapeutic targets; Tyrosine; Virology
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-022-01751-y

Erlotinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Overcoming erlotinib resistance is crucial to improve the survival of advanced non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. It is also an important clinical problem that urgently needs a solution. In this study, we explored strategies to overcome erlotinib resistance from the perspective of energy metabolism. SIRT6 is a histone deacetylase. Here, we found that high expression of SIRT6 is associated with poor prognosis of lung adenocarcinoma, especially in EGFR-mutated NSCLC patients. The next cell experiment found that SIRT6 expression increased in erlotinib-resistant cells, and SIRT6 expression was negatively correlated with the sensitivity of NSCLC to erlotinib. Inhibition of SIRT6 promoted erlotinib-induced apoptosis in erlotinib-resistant cells, and glycolysis in drug-resistant cells was also inhibited. Functional studies have shown that SIRT6 increases glycolysis through the HIF-1α/HK2 signaling axis in drug-resistant cells and inhibits the sensitivity of NSCLC cells to erlotinib. In addition, the HIF-1α blocker PX478-2HCL attenuated the glycolysis and erlotinib resistance induced by SIRT6. More importantly, we confirmed the antitumor effect of SIRT6 inhibition combined with erlotinib in NSCLC-bearing mice. Our findings indicate that the cancer metabolic pathway regulated by SIRT6 may be a new target for attenuating NSCLC erlotinib resistance and has potential as a biomarker or therapeutic target to improve outcomes in NSCLC patients.