Functional characterization of a low-frequency V1937I variant in FASN associated with susceptibility to esophageal squamous cell carcinoma
- 9 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Archives of Toxicology
- Vol. 94 (6), 2039-2046
- https://doi.org/10.1007/s00204-020-02738-x
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.Keywords
Funding Information
- National Natural Science Foundation of China (81872696)
- National Program for Support of Top-notch Young Professionals
- the Young Elite Scientist Sponsorship Program by CAST (2018QNRC001)
- the Natural Science Foundation of Hubei Province for Innovative Research Groups (2019CFA009)
- National Key Research and Development Plan Program (2016YFC1302702, 2016YFC1302703)
- Program for HUST Academic Frontier Youth Team
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