Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance

Abstract

Abstract. The lipid metabolic enzymes are considered candidate therapeutic targets for breast cancer. Long-chain acyl-coenzyme A (CoA) synthase (ACSL) is one of lipid metabolic enzymes and converts free-fatty acid to fatty acid-CoA. Five ACSL isoforms including ACSL1, ACSL3, ACSL4, ACSL5 and ACSL6 are identified in human. High ACSL4 expression has been observed in aggressive breast cancer phenotype. However, the role of other isoforms is still little-known. We therefore, analyzed the expression of ACSL isoforms in each subtype of breast cancer within METABRIC dataset and cancer cell line encyclopedia dataset. The expression levels of ACSL1, ACSL4 and ACSL5 in estrogen receptor (ER)-negative group were higher than that in ER-positive group. Similar expression pattern was detected among breast cancer cell lines MCF-7 (ER-positive) and MDA-MB-231 (ER-negative). Treatment of ACSL inhibitor triacsin C which inhibited enzyme activity of ACSL 1, 3, 4 and 5 suppressed cell growth of MCF-7 and MDA-MB-231. Our results further showed that high ACSL5 expression was associated with good prognosis in patients with both ER-positive and ER-negative breast cancer through KM plotter analysis. These results suggest that ACSL1, ACSL4 and ACSL5 expression is regulated by ER signaling pathways and ACSL5 is a potential novel biomarker for predicting prognosis of breast cancer patients.

Fatty acid activation in carcinogenesis and cancer development: Essential roles of long‑chain acyl‑CoA synthetases (Review)

“…A recent bioinformatics study (37) utilizing online databases Oncomine (https://www.oncomine.org/resource/login .html) and PrognoScan (http://www.abren.net/PrognoScan/) stated certain novel associations between ACSL expression and cancer survival outcomes. On the one hand, which was in line with previous findings (12,18,27), the study showed that the overexpression of either ACSL1 or ACSL4 was associated with a poorer prognosis in patients with colon cancer, and that ACSL5 downregulation was associated with poor survival in breast cancer patients. On the other hand, the study suggested certain novel links.…”

“…By contrast, ACSL5 appears to exhibit the opposite function in cancer. ACSL5 was downregulated in colon (26) and breast (27) cancer, where ACSL1 and ACSL4 were upregulated. ACSL5 was also decreased in bladder cancer (28).…”

“…ACSL5 was also decreased in bladder cancer (28). More importantly, lower expression of ACSL5 in breast cancer was associated with a worse prognosis (27). An exception was reported in glioma, where ACSL5 was upregulated (29).…”

“…These two enzymes participate in lipid anabolism and catabolism. By contrast, ACSL5 [another ACSL member which drives lipid biosynthesis rather than fatty acid oxidation (10)] was downregulated in breast and prostate cancer (26,27). It is thus tentative to propose that ACSL1-and ACSL4-mediated lipid catabolism are useful for cancer promotion.…”

Development and validation of a lipogenic genes panel for diagnosis and recurrence of colorectal cancer

“…ACSL5 is a member of Acyl-CoA synthetase long-chain family that unlike the other members of ACSL family, provokes β-oxidation [31] or triacylglycerols storage [32] due to its cellular location. ACSL5 dysregulation was previously reported in bladder cancer [33], breast cancer [33,34], glioma [35], glioblastomas [36], and pancreatic ductal adenocarcinoma [37]. Meanwhile, the expression status of ACSL5 in CRC tumors is vague.…”