SLC27A5 Deficiency Promotes Hepatoma Proliferation Through NRF2/TXNRD1 Axis

HCC is one of the most prevalent cancers worldwide,and China accounts for more than half of initially diagnosed cases.However,surgical resection or targeted therapy have limited therapeutic benefits for advanced liver cancer.HCC is a highly malignant tumor characterized by high drug resistance,phenotypic and molecular heterogeneity.Risk factors include hepatitis B and C infection and aflatoxin are the most common risk factors of HCC,moreover,recent studies have found that the incidence of liver cancer in obese patients is 83%-89% higher than those of normal-weight people,suggesting that metabolic abnormalities are associated with HCC.Therefore,to exploit metabolic alterations and identify molecular features that define or contribute to HCC progression remains clinically urgent.Meanwhile,the development of novel therapeutic strategies are highly desirable.Based on a total of 521 human HCC gene expression profiles across 8 microarray datasets,Zeribe Chike Nwosu et al found that many metabolic genes of potential clinical relevance are consistently deregulated in human HCC regardless of the etiological background.Such as,Glycolytic targets ALDOB,HK2;Fatty acid targets LPIN2,MTTP,FAAH;Gluconeogenesis targets PCK1,G6 PC.Over 60% of these metabolic genes have not been previously acknowledged.We further analyzed both GEO(GSE117822,Gene Expression Profiling of Hepatocellular Carcinoma)and TCGA dataset,and identified significantly down-regulated gene SLC27A5,which is involved in fatty acid transport and bile acid metabolism.This study aimed to investigate the role of SLC27A5 in hepatocellular carcinoma(HCC)and to explore potential therapeutic strategies.We found that SLC27A5 expression was significantly downregulated in HCC tumors in an independent cohort of 373 HCC samples from the TCGA Liver Hepatocellular Carcinoma(LIHC)dataset.Moreover,the lower SLC27A5 expression contributes to disease progression and predicts poor prognosis of HCC.We detected that promoter hypermethylation might be one of the reasons for SLC27A5 suppression.Overexpression of SLC27A5 significantly repressed the hepatoma cell proliferation,while knockout of SLC27A5 promoted hepatoma cell proliferation in vitro and in vivo.These studies clearly demonstrated that SLC27A5 functions as a tumor suppressor.SLC27A5 plays an important role in lipid metabolism,lipidomics unraveled that loss of SLC27A5 increases polyunsaturated lipids,induces ROS production and lipid peroxidation including the malondialdehyde(MDA)level and 4-hydroxynonenal(4-HNE)-induced protein modification.Mechanistically,Mass spectrometry analysis found that 4-HNE directly modifies cysteine residues(Cys513,518)on KEAP1,thus leading KEAP1/NRF2 pathway activation and induction of downstream TXNRD1 expression.Finally,NRF2 blockade with brusatol or TXNRD1 silencing(shTXNRD1)or the TXNRD1 inhibitor auranofin combined with sorafenib significantly promotes apoptosis and inhibits HCC growth,indicated that a combination of sorafenib with NRF2/TXNRD1 inhibition has synergistic anti-tumor effects in SLC27A5-deficient hepatoma cells.In conclusion,we demonstrated that SLC27A5 acts as a novel tumor suppressor by suppressing TXNRD1 expression via KEAP1/NRF2 pathway in HCC.Blockade of NRF2/TXNRD1 sensitizes SLC27A5 deficient hepatoma cells to sorafenib treatment.Our study first demonstrated that SLC27A5 deficiency is critical to the induction ROS production and lipid peroxidation and activation of KEAP1/NRF2 pathway and promotes hepatoma proliferation,providing a mechanistic link between disrupted lipid metabolism and redox homeostasis.Combination therapy of sorafenib and NRF2 or TXNRD1 inhibitors may be a potential strategy in HCC treatment.