Abstract
Metabolic reprogramming has been regarded as one of the core hallmarks of cancer and increased de novo fatty acid synthesis has been documented in multiple tumors including esophageal squamous cell carcinoma (ESCC). Our previous exome-wide analyses found a Val1937Ile variant (rs17848945) in the 34th exon of fatty acid synthase (FASN) that showed a strong association with the risk of ESCC. In this study, we performed a series of functional assays to investigate the biological functions underlying this variant in the development of ESCC. We demonstrated that FASN was upregulated in ESCC and both knockdown and knockout of FASN significantly inhibited ESCC cell proliferation, suggesting a tumor promoter role for this gene in ESCC. Furthermore, the results showed that overexpression of FASN[I] in the ESCC cells substantially enhanced cell proliferation, compared with overexpression of FASN[V], or the control vector. Intriguingly, we found that the FASN[I] variant can enhance the enzyme activity of FASN, and, thus, increase the amount of the FASN end-product, palmitate in the ESCC cells. We also observed elevated palmitate levels in the plasma of the FASN[I] genotype carriers among a total of 632 healthy Chinese adults. In conclusion, our results suggested that the FASN V1937I variant influenced ESCC cell proliferation and susceptibility by altering the catabolic activity of FASN on palmitate. These findings may highlight an important role of palmitate metabolism in the development of ESCC and may contribute to the personalized medicine of this disease.
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Acknowledgements
We gratefully acknowledge the members of the Miao lab and Prof. Ying Gao’s group for the suggestions and contributions to this work. This work was supported by National Natural Science Foundation of China (81872696 to Jiang Chang); National Program for Support of Top-notch Young Professionals to Jiang Chang; the Young Elite Scientist Sponsorship Program by CAST (2018QNRC001 to Jiang Chang); the Natural Science Foundation of Hubei Province for Innovative Research Groups (2019CFA009 to Xiaoping Miao); National Key Research and Development Plan Program (2016YFC1302702, 2016YFC1302703 to Xiaoping Miao); National Program for Support of Top-notch Young Professionals and Program for HUST Academic Frontier Youth Team to Xiaoping Miao.
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All procedures involving human participants were in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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Data on plasma palmitate levels were obtained from Peiqin Li et al.’s study (Li et al. 2018) and the study design was approved by the Institutional Review Board of the Chinese Center for Disease Control and Prevention. RNA-seq data of FASN were obtained from our previous study (Chang et al. 2017) and the study was approved by the Institutional Review Board of the Chinese Academy of Medical Sciences, Cancer Institute and Zhejiang Cancer Hospital. All participants gave written informed consent.
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Wang, X., Tian, J., Zhao, Q. et al. Functional characterization of a low-frequency V1937I variant in FASN associated with susceptibility to esophageal squamous cell carcinoma. Arch Toxicol 94, 2039–2046 (2020). https://doi.org/10.1007/s00204-020-02738-x
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DOI: https://doi.org/10.1007/s00204-020-02738-x