Genetic Alteration, Prognostic and Immunological Role of Acyl-CoA Synthetase Long-Chain Family Member 4 in a Pan-Cancer Analysis

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.

Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism

“…According to a systematic study of the Oncomine and UALCAN databases, compared with normal tissues, ACSL4 is downregulated in breast cancer (BC), bladder cancer, brain cancer, leukemia, and lung cancer (LC), but upregulated in liver cancer, colorectal cancer, head and neck cancer, myeloma, ovarian cancer, and kidney cancer [116,117] . In addition, a comprehensive analysis of PrognoScan, the Kaplan–Meier mapping database, and Gene Expression Profiling Interactive Analysis revealed that low ACSL4 expression generally predicts a good prognosis across cancers despite the poor prognostic results in several certain cancers [117] . In addition, ACSL4 is negatively correlated with deoxyribonucleic acid (DNA) methylation levels and positively correlated with immune infiltration in most cancers [117] .…”

Ferroptosis: Opportunities and Challenges in Treating Endometrial Cancer

“…Qin et al (2021) reported that SLC7A11 was associated with prolonged survival time of endometrial cancer, which suggested a protective factor. While CDKN1A was found to be an activator of ferroptosis, which was significantly associated with better prognosis of endometrial cancer (Yamawaki et al, 2017); and ACSL4 was associated with lipid metabolism and lipid peroxidation dependent ferroptosis, while the low expression of ACSL4 was -miR-146a-5p, hsa-mir-708-5p, hsa-miR-4746-5p, hsa-miR-452-5p, hsa-miR-452-3p, hsa-miR-224-5p, hsa-miR-375-3p, hsa-miR-30a-5p, hsa-miR-598-3p, hsa-miR-335-3p, hsa-miR-30c-5p, hsa-miR-101-5p, hsa-miR-210-3p ,hsa-miR-676-3p, hsa-miR-130a-3p, hsa-miR-1266-5p, hsa-miR-1271-5p ,hsa-miR-130a-5p, hsa-miR-203b-3p, hsa-mir-3074-5p, and hsa-miR-30d-5p Risk score = hsa-miR-146a-5p * 0. observed in endometrial cancer to be associated with better prognosis (Yu et al, 2022). Intriguingly, quite a few research studies have probed into the regulated mechanism of ferroptosis-associated genes in endometrial cancer, as indicated by the evidence that ferroptosis-associated genes were positively related to M1 macrophages, M2 macrophages, T cell follicular helper, and B cells naive, while they were negatively related to NK cells activated, T cells regulatory (Tregs) and neutrophils ; and that damage-associated molecular patterns (DAMPS) released by ferroptosis were sensed by the immune cells, thus enhancing inflammatory responses and improving the immune microenvironment in cancer was found (López-Janeiro et al, 2021).…”

Emerging mechanisms of ferroptosis and its implications in lung cancer

“…[26,67] ACSL4 expression is linked to immune cell infiltration. [68] IFN-γ secreted by CD8 + T cells and AA were shown to promote ACSL4-mediated ferroptosis. [69] Therefore, the relationship between ACSL4-mediated ferroptosis and immune infiltration and the impact on the efficacy of antitumor therapy should be the focus of future studies.…”