It has been shown that lipid metabolic reprogramming is a novel hallmark of malignancy, and in human cancers, lipid synthesis is significantly increased to meet the needs of rapid tumor cell proliferation21,22 FASN is a multifunctional enzyme that plays a key role in lipid synthesis and mainly catalyzes the synthesis of palmitic acid 23. FASN is expressed at low levels in normal tissues and cells. However, its expression is significantly increased in tumor cells, including gastric cancer24, breast cancer 25, esophageal squamous cell carcinoma26, and hepatocellular carcinoma 27, which also suggests a possible correlation between FASN overexpression and tumor development. Our study found that FASN expression was significantly upregulated in most tumors in the TCGA project, but the expression of FASN protein levels was significantly lower in breast cancer, Lung adenocarcinoma, and ovarian cancer in the CPTAC dataset. Previously reported FASN protein expression was also significantly reduced in UCEC 28. This suggests that the expression level of FASN mRNA in tumors may not parallel the expression level of protein. However, whether the dysregulation of FASN expression in cancer is a common phenomenon and whether it promotes similar pathogenesis of tumors remains to be further verified.
Survival analysis revealed that FASN expression in different tumors had different prognostic responses in different tumors, and high FASN expression was associated with poorer OS and DFS in several tumor cases, and overexpression of FASN in Breast Cancer, gastric adenocarcinoma, CHOL(Cholangiocarcinoma), and colorectal cancer was previously reported to be negatively correlated with OS prognosis25,29−31. However, our study did not find that FASN expression correlated with OS prognosis in the above cancers, and the difference between them may be due to the continuous updating of the data, and surprisingly, high expression of FASN correlated with good OS, DFS in LGG(Brain Lower Grade Glioma).
FASN may be involved in tumor progression through multiple regulatory mechanisms. Analysis of this study showed that FASN had the highest frequency of missense mutations in SKCM, while almost all of them were amplification mutations in MESO. Further study revealed that mutations in FASN were associated with the prognosis of some tumor cases, and FASN mutations were positively correlated with DSS, OS, and PFS in UCEC patients, but mutations in FASN were not correlated with the prognosis of STAD patients. This may speculate that the low expression of FASN caused by mutation of the gene is associated with good DSS, OD, and PFS in UCEC.
We also analyzed the levels of total protein and phosphorylated protein of FASN in breast, renal clear cell carcinoma, and lung adenocarcinoma, and our findings showed that the phosphorylation sites of FASN were significantly lower in breast and renal clear cell carcinoma, but significantly higher in lung adenocarcinoma compared with adjacent normal tissues. The levels of total FASN protein and phosphorylation levels were consistent in breast cancer expression, while the trends were not the same in UCEC. Based on these results, it is speculated that the inconsistent trends between FASN mRNA expression and total protein levels, and phosphorylation levels may be influenced by other factors and need to be further explored. Previous studies have found that phosphorylation of FASN leading to increased FASN enzyme activity is associated with breast cancer progression 32. This is similar to our findings. DNA methylation is one of the most important forms of mammalian epigenetic modifications 33. Epigenetic dysregulation leads to the activation or inhibition of multiple signaling pathways, which may promote cancer progression34. In this study, we found that DNA methylation of FASN was significantly reduced in HNSC, PRAD, THCA, and UCEC. In addition, tumor immune infiltrating cells play an important role in the development of tumors35. Further analysis showed that FASN expression in BRCA, CESC, KIRC, KIRP, LUSC, OV, and UVM was positively correlated with cancer-associated fibroblasts.
Dysregulation of FASN expression in tumors is associated with the disruption of multiple pathways and signaling pathways associated with various cancers. Inhibition of FASN synthesis inhibits DNA synthesis and significantly attenuates cell cycle progression36.To gain a more comprehensive understanding of the potential mechanisms of the role of FASN in tumor development, gene enrichment analysis revealed that genes associated with FASN expression were mainly enriched in the PPAR(peroxisome proliferator-activated receptors) signaling pathway, Spinocerebellar ataxia, and Proteasome. PPAR activation activates or represses gene transcription through recognition of target gene promoters or PPAR response elements and participates in metabolic processes, such as lipid metabolism and fatty acid metabolism37–39. PPARα promotes fatty acid metabolism in hepatocellular carcinoma cells through activation of FASN40. This is similar to our results. In addition, we found that the expression of FASN was significantly correlated with GPAM, SCD, CIDEC, DGAT2, and AGPAT2 genes.
This study is based on a bioinformatics database analysis of FASN and lacks actual clinical patient studies, which still need exact and valid experiments for further validation.