FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

Dong,Zhen; Yang,Jie; Li,Lin; Tan,Li; Shi,Pengfei; Zhang,Jiayi; Zhong,Xi; Ge,Lingjun; Wu,Zonghui; Cui,Hongjuan

doi:10.3892/ijo.2020.4964

FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

Authors:
- Zhen Dong
- Jie Yang
- Lin Li
- Li Tan
- Pengfei Shi
- Jiayi Zhang
- Xi Zhong
- Lingjun Ge
- Zonghui Wu
- Hongjuan Cui
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Affiliations: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing 400716, P.R. China, Hospital of Southwest University, Southwest University, Chongqing 400716, P.R. China
Published online on: January 17, 2020 https://doi.org/10.3892/ijo.2020.4964
Pages: 728-742
Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Melanoma, the most aggressive human skin tumor, has a very short survival time, and there are currently no effective treatments. Alterations in cell metabolism, such as enhanced aerobic glycolysis, have been identified as hallmarks of cancer cells. In the present study, bioinformatics studies using online databases revealed that FOXO3a expression was lower in melanoma tissues compared with normal tissues and nevus. Additionally, Kaplan‑Meier analysis showed that high expression of FOXO3a predicted an improved prognosis for patients with melanoma. Furthermore, Pearson correlation analysis indicated that the expression of FOXO3a was positively correlated with SIRT6 expression and negatively correlated with the expression levels of a number of glycolysis‑associated genes. Chromatin immunoprecipitation and luciferase assays showed that FOXO3a was enriched in the SIRT6 promoter region and promoted its transcription. Then, SIRT6 was overexpressed in FOXO3a‑knockdown MV3 cells and downregulated in FOXO3a‑overexpressing MV3 cells by using lentivirus‑mediated stable infection. The results showed that SIRT6 knockdown or overexpression rescued the effects of FOXO3a overexpression or knockdown, respectively, on glycolysis, as determined by glucose uptake, glucose consumption and lactate production assays, the expression of glycolytic genes and glucose stress flux tests. SIRT6 overexpression also suppressed FOXO3a knockdown‑induced tumor growth in a mouse model. The present findings indicated that the FOXO3a‑SIRT6 regulatory axis inhibited glucose metabolism and tumor cell proliferation in melanoma, and provided novel insight into potential therapeutic strategies to treat this disease.

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