Dataset Information

The SIRT6-Autophagy-Warburg Effect Axis in Papillary Thyroid Cancer.

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.

SUBMITTER: Yang Z

PROVIDER: S-EPMC7485319 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The SIRT6-Autophagy-Warburg Effect Axis in Papillary Thyroid Cancer.

Yang Zhou Z Huang Renhong R Wei Xiyi X Yu Weiping W Min Zhijun Z Ye Min M

Frontiers in oncology 20200828

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) <i>in vitro</i>, thus increasing reactive oxygen species (ROS) production. The a ...[more]

PMID: 32983963

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Project description:BackgroundDespite a good and overall prognosis, papillary thyroid cancer (PTC) can still affect the quality of life of many patients, and can even be life-threatening due to its invasiveness and metastasis. Emerging studies demonstrate that circular RNAs (circRNAs) participate in the regulation of various cancers. However, the circRNA profile in invasive PTC is still not well understood.MethodsCompeting endogenous RNA (ceRNA) microarrays were performed to determine circRNAs contributed to the tumorigenesis and invasiveness of PTC. Bioinformatics methods were used to narrow down the candidate circRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) assays revealed a significant upregulation of hsa_circ_0058124 in PTC tissue and a close correlation with a poor prognosis for PTC patients. RNA fluorescence in situ hybridization and Cell fractionation assay were used to investigate the subcellular location of hsa_circ_0058124. Then, we examined the functions of hsa_circ_0058124 in PTC by cell proliferation, cell cycle, apoptosis, migration and invasion assay. Mechanistically, RNA sequencing and GSEA analysis were applied to predict the downstream pathway of hsa_circ_0058124. Dual-luciferase report assays were used to explore the potential miRNA sponge role of hsa_circ_0058124. Western blotting, cell proliferation, cell cycle, cell apoptosis, migration and invasion, and mouse xenograft assay were used to validate the effects of hsa_circ_0058124/NOTCH3/GATAD2A axis on PTC progression.ResultsIn the current study, a novel hsa_circ_0058124 on 2q35 was identified and explored in PTC. Hsa_circ_0058124 is associated with the malignant features and poor outcomes of PTC patients. Hsa_circ_0058124 acts as an oncogenic driver that promotes PTC cell proliferation, tumorigenicity, tumor invasion, and metastasis, which functions as a competing endogenous RNA to modulate miRNA-218-5p and its target gene NUMB expression, and consequently with repression of the NOTCH3/GATAD2A signaling axis in vitro and in vivo.ConclusionsThis study unveils a novel biomarker panel consisting of the hsa_circ_0058124/NOTCH3/GATAD2A axis which is critical for PTC tumorigenesis and invasiveness and may represent a novel therapeutic target for intervening in PTC progression.

Dataset Information

The SIRT6-Autophagy-Warburg Effect Axis in Papillary Thyroid Cancer.

Publications

The SIRT6-Autophagy-Warburg Effect Axis in Papillary Thyroid Cancer.

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