Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells

Abstract

Acyl-CoA synthetase 4 (ACSL4) overexpression plays a causal role in the aggressiveness of triple negative breast cancer. In turn, a negative correlation has been established between ACSL4 and estrogen receptor alpha (ERα) expression. However, the upstream regulatory mechanisms leading to differential ACSL4 expression between triple negative breast cancer and ERα-positive cells remained unknown. We performed the characterization of the human ACSL4 promoter and the identification of transcription factors involved. Deletional analysis demonstrated the proximal 43 base pairs of the promoter are involved in overexpression. By site directed mutagenesis we describe that retinoid-related orphan receptor alpha (RORα), Sp1 and E2F elements are involved in the promoter activity. We established for the first time that estrogen-related receptor alpha (ERRα) is a transcription factor involved in the higher activation of the human ACSL4 promoter in breast cancer cells. Furthermore, a combination of inhibitors of ACSL4 and ERRα produced a synergistic decrease in MDA-MB-231 cell proliferation. We also demonstrated that ERα restoration in triple negative breast cancer cells downregulates ACSL4 expression. The results presented in this manuscript demonstrated transcriptional mechanism is involved in the different expression of ACSL4 in human breast cancer cell lines of different aggressiveness.

Targeting ferroptosis in breast cancer

“…In 2019, Dattilo found that the retinoid-related orphan receptor alpha (RORα), specificity protein 1 (Sp1) and E2F elements were involved in the promoter activity of ACSL4, and oestrogen-related receptor alpha (ERRα) was a transcription factor involved in activation of the human ACSL4 promoter. They also demonstrated that ERα restoration was able to downregulate ACSL4 expression in triplenegative breast cancer cells [294]. In contrast, Belkaid et al found that 17β-oestradiol treatment upregulated the level of ACSL4 by increasing its half-life, and it promoted an invasive phenotype in an ACSL4-dependent manner in the oestrogen receptor-positive breast cancer cell lines MCF7 and T47D [295].…”

Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases

“…It is important to note that altered expression of ACSL3 and ACSL4 is not unique to hepatic malignancies. Up-regulated ACSL4 expression has been previously characterised in extrahepatic cancers such as colon adenocarcinoma [71], lung [5,39], breast [34,35,41,72,73] and prostate cancers [72]. Increased ACSL4 expression is a determinant of drug resistance in metastatic breast cancer cells where altered cellular energetics leads to increased expression of the ATP-binding cassette (ABC) transporter, which mediates the egress of chemotherapeutic molecules [35].…”

“…ACSL4 is also associated with the ER and lipid droplets [30,31] but endosomal [32], plasma membrane [30], peroxisomal [33] and secretory vesicle [29] localisations have also been reported. Importantly, there is emerging evidence that dysregulated expression of both ACSL3 and ACSL4 is associated with disease and especially with cancer [15,28,[34][35][36][37][38]. ACSL3 can promote cancer cell survival through amplified fatty acid β-oxidation [5,37] and increased arachidonic acid-dependent prostaglandin synthesis [39], both of which can drive tumour growth.…”

ACSL4 as a Potential Target and Biomarker for Anticancer: From Molecular Mechanisms to Clinical Therapeutics

“…ACSL4 activate long chain fatty acids to initiate a number of intracellular lipid metabolic pathways ( Kuwata and Hara, 2019 ; Rossi Sebastiano and Konstantinidou, 2019 ). Emerging evidences showed that dysregulated expression of ACSL4 was tightly associated with various diseases and especially with cancers ( Dattilo et al, 2019 ; Orlando et al, 2019 ; Rossi Sebastiano and Konstantinidou, 2019 ). Mechanisms of ACSL4 involvement in tumor development may include iron-dependent, non-apoptotic, and cell death pathways ( Doll et al, 2017 ), drug resistance caused by metabolic recombination ( Orlando et al, 2019 ), arachidonic acid-dependent tumorigenesis ( Orlando et al, 2012 ), steroid production ( Wang et al, 2019 ) and activation of intracellular pro-cancer signaling pathways ( Wu et al, 2015 ).…”