Upregulating sirtuin 6 ameliorates glycolysis, EMT and distant metastasis of pancreatic adenocarcinoma with krüppel-like factor 10 deficiency.
2021
Kruppel-like factor 10 (KLF10) is a tumor suppressor in multiple cancers. In a murine model of spontaneous pancreatic adenocarcinoma (PDAC), additional KLF10 depletion accelerated distant metastasis. However, Klf10 knockout mice, which suffer from metabolic disorders, do not develop malignancy. The mechanisms of KLF10 in PDAC progression deserve further exploration. KLF10-depleted and KLF10-overexpressing PDAC cells were established to measure epithelial-mesenchymal transition (EMT), glycolysis, and migration ability. A murine model was established to evaluate the benefit of genetic or pharmacological manipulation in KLF10-depleted PDAC cells (PDACshKLF10). Correlations of KLF10 deficiency with rapid metastasis, elevated EMT, and glycolysis were demonstrated in resected PDAC tissues, in vitro assays, and murine models. We identified sirtuin 6 (SIRT6) as an essential mediator of KLF10 that modulates EMT and glucose homeostasis. Overexpressing SIRT6 reversed the migratory and glycolytic phenotypes of PDACshKLF10 cells. Linoleic acid, a polyunsaturated essential fatty acid, upregulated SIRT6 and prolonged the survival of mice injected with PDACshKLF10. Modulating HIF1α and NFκB revealed that EMT and glycolysis in PDAC cells were coordinately regulated upstream by KLF10/SIRT6 signaling. Our study demonstrated a novel KLF10/SIRT6 pathway that modulated EMT and glycolysis coordinately via NFκB and HIF1α. Activation of KLF10/SIRT6 signaling ameliorated the distant progression of PDAC. Clinical Trial Registration: ClinicalTrials.gov. identifier: NCT01666184. Boosting the activity of a tumor suppressor pathway in pancreatic cancer may reduce the risk of metastasis. Reduced expression of a tumor suppressor gene called Kruppel-like factor 10 (KLF10) is found in breast, lung and pancreatic cancers. KLF10 deficiency in pancreatic cancer is linked to accelerated cancer progression and metastasis, but the underlying mechanisms are unclear. In experiments on mouse models and human cell cultures, Hui-Ju Ch’ang at the National Institute of Cancer Research in Zhunan, Taiwan, and co-workers found that KLF10 binds to and upregulates another tumor suppressor gene, SIRT6. This second gene mediates KLF10 activity, including its role in regulating glucose metabolism and a process that transforms epithelial cells into cells with invasive, migratory characteristics. Overexpressing SIRT6 in KLF10-deficient cells reversed glycolysis, migratory cell behavior and reduced metastasis, suggesting a potential treatment option.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
48
References
0
Citations
NaN
KQI