SLC27A5 deficiency activates NRF2/TXNRD1 pathway by increased lipid peroxidation in HCC.

Cell Death and Differentiation
Qingzhu GaoNi Tang

Abstract

Solute carrier family 27 member 5 (SLC27A5/FATP5) is involved in fatty acid transport and bile acid metabolism; however, little is known about its role in human diseases. Here, we first show that SLC27A5 expression is downregulated in hepatocellular carcinoma (HCC) by DNA hypermethylation, and reduced SCL27A5 expression contributes to tumor progression and poor prognosis. Both gain- and loss-of-function studies demonstrated that SLC27A5 has an antiproliferative effect on HCC cells in vitro and in vivo. Knockout of SLC27A5 increases polyunsaturated lipids, leading to increased NADP+/NADPH ratio, ROS production as well as lipid peroxidation and the subsequent accumulation of 4-hydroxy-2-nonenal (4-HNE) in hepatoma cells. Mass spectrometry analysis found that 4-HNE directly modifies cysteine residues (Cys513, 518) on KEAP1, thus leading KEAP1/NRF2 pathway activation and increases the expression levels of NRF2 target genes, such as TXNRD1. Further, SLC27A5 expression negatively correlates with TXNRD1 expression in hepatoma cells and clinical HCC samples, and blockade of NRF2/TXNRD1 using genetic approaches or inhibitors sensitizes SLC27A5-deficient hepatoma cells to sorafenib treatment. Collectively, we demonstrated that SLC27A5 ac...Continue Reading

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Citations

Apr 23, 2020·International Journal of Molecular Medicine·Yu Zhang, Hongyan Zhou
Apr 8, 2021·Journal of Hepatocellular Carcinoma·Jialei WengNing Ren
Oct 20, 2021·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Yi-Te LeeVatche G Agopian
Dec 3, 2021·Journal of Clinical Laboratory Analysis·Kaixiang FengDetao Yin

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Methods Mentioned

BETA
Assay
PCR
flow cytometry
MDA
xenograft
immunoprecipitation
nuclear translocation
xenografts

Software Mentioned

SPSS
IncuCyte ZOOM
Pannoramic Viewer
Image
GraphPad
Maxquant
ImageJ
Image Pro Plus
Pro plus
GraphPad Prism

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