Abstract
Acyl-CoA Synthetase long-chain family member 4 (ACSL4) is a member of acyl-CoA synthetase protein long-chain family, which is associated with amino acid synthesis, lipid synthesis and lipid peroxidation dependent iron death. However, the role of ACSL4 in generalized carcinoma remains unclear. We aim to analyze the expression and prognostic value of ACSL4 in pan-cancer, and further explore the correlation between ACSL4 and immune infiltration. Through ONCOMINE, TIMER (Tumor Immune Estimation Resource), GEPIA (Gene expression Profiling Interactive), UALCAN and HPA, ACSL4 expression patterns of in pan-cancer were analyzed. The prognostic value of ACSL4 was analyzed using PrognoScan and Kaplan-Meier Plotter databases. Furthermore, gene variation and epigenetic modification of ACSL4 were analyzed by cBioPortal and GSCA databases. Meanwhile, GEPIA and TIMER databases applied to evaluate the relationship between ACSL4 expression and immune infiltration. These results indicate that ACSL4 expression is down-regulated and associated with prognosis in most tumors. In general, lower ACSL4 expression shows more beneficial prognosis. The most common genetic alteration of ACSL4 is point mutation. ACSL4 is negatively correlated with DNA methylation levels in most cancers. ACSL4 mutations or hypomethylation are associated with poor prognosis. In addition, ACSL4 is positively correlated with immune infiltration in cancers. ACSL4 and immune infiltration are strongly associated with prognosis in BRCA (Breast invasive carcinoma) and SKCM (Skin Cutaneous Melanoma). ACSL4 mutation caused significant changes of immune infiltration in UCEC (Uterine Corpus Endometrial Carcinoma) and SARC (Sarcoma). ACSL4 may be a promising prognostic biomarker for pan-cancer and is closely associated with immune infiltration in the tumor microenvironment.
Highlights
Cancer relies on metabolic reprogramming to drive malignant transformation (Boroughs and DeBerardinis, 2015)
The results showed that compared with normal tissues, Acyl-CoA Synthetase long-chain family member 4 (ACSL4) expression was higher in colorectal cancer, head and neck cancer, kidney cancer, liver cancer, lymphoma, myeloma, and pancreatic cancer, but decreased in bladder cancer, brain and CNS cancer, breast cancer, leukemia, lung cancer, and pancreatic cancer
ACSL4 was Significantly decreased in BRCA Breast invasive carcinoma, KICH, KIRP, GBM, PAAD, SKCM, KIRC, PRAD and UCEC (p < 0.05)
Summary
Cancer relies on metabolic reprogramming to drive malignant transformation (Boroughs and DeBerardinis, 2015). Each with unique substrate of the ACSL family preferences and enzyme activity at different cellular sites, which depended on the chain length and saturation status of fatty acids (Grevengoed et al, 2014). ACSL4 prefers longer polyunsaturated fatty acids (PUFA) as substrates, such as arachidonic acid. It catalyzes the conversion of free arachidonic acid to arachidonic acid-coA ester, which is esterified by interaction with membrane phospholipids and leads to ferroptosis (Küch et al, 2014; Kagan et al, 2017; Sánchez-Martínez et al, 2017). Ferroptosis is a new iron-dependent form of regulated cell death,which characterized by iron-dependent accumulation of lipid-ROS and subsequent depletion of polyunsaturated fatty acid phospholipids (PUFA-PLS) (Hirschhorn and Stockwell, 2019). ACSL4 has been shown to be overexpressed in several cancer types, including colon cancer, breast cancer, liver and prostate cancer (Sánchez-Martínez et al, 2017; Wang J. et al, 2020; Chen et al, 2020; Ma et al, 2021; Sha et al, 2021), but often downregulated in gastric cancer and lung cancer (Ye et al, 2016; Zhang et al, 2021)
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