Abstract
As shown in our previous study, SIRT6 promotes an aggressive phenotype and the epithelial-mesenchymal transition (EMT) in papillary thyroid cancer (PTC). In this study, we focused on the regulatory axis including SIRT6, autophagy, and the Warburg effect. We innovatively confirmed that SIRT6 overexpression depleted histone H3 lysine 56 acetylation (H3K56ac) of the negative regulator of reactive oxygen species (NRROS) in vitro, thus increasing reactive oxygen species (ROS) production. The accumulated ROS then activated endoplasmic reticulum stress (ER stress) and subsequently induced autophagy. Furthermore, SIRT6 overexpression inhibited glucose transporter 1 (GLUT1) via autophagy-mediated degradation, ultimately suppressing the Warburg effect. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC, 5 mM) or the autophagy inhibitor chloroquine (CQ) both rescued the inhibition of the Warburg effect. Additionally, a higher concentration of NAC (15 mM) further inhibited the Warburg effect. These concentration-dependent bilateral effects of NAC on this process were confirmed to be due to the regulation of the AMPK signaling pathway. Finally, we further examined this mechanism in vivo by establishing subcutaneous xenografts in nude mice and analyzed the tumors using 18F radio-labeled fluorodeoxyglucose (18F-FDG) PET/CT. In conclusion, we identified a SIRT6-ROS-ER stress-autophagy-GLUT1-Warburg effect axis in PTC, which may provide a new therapeutic target. In addition, NAC (low concentration) and CQ, previously considered to be tumor inhibitors, were shown to promote tumorigenesis in PTC with high SIRT6 expression by inducing the Warburg effect.
Highlights
Thyroid cancer is a common malignant tumor, including papillary, follicular, undifferentiated, and medullary pathological types
The specific mechanism underlying the interaction of autophagy and the Warburg effect in papillary thyroid carcinoma (PTC) remains unclear, we focused on the regulatory axis of the SIRT6autophagy-Warburg effect
The mRNA expression of the autophagy-associated genes Beclin1, ATG7, VPS34, BNIP3, and ATG4B was significantly upregulated in TPC1SIRT6 cells compared with TPC1-NC cells
Summary
Thyroid cancer is a common malignant tumor, including papillary, follicular, undifferentiated, and medullary pathological types. Among these types, papillary thyroid carcinoma (PTC) is the most common pathological type, accounting for 85% of the total number of cases [1]. The incidence of PTC has recently increased annually [2]. Advances in early detection have improved the prognosis of patients with PTC, but some patients with thyroid cancer still experience a lower benefit and a lower survival rate. New targets and new diagnostic markers for PTC are urgently needed [3]
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