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.
Highlights
It has been demonstrated that Acyl-CoA synthetase 4 (ACSL4) enzyme expression is elevated in cancer cells, which promotes an aggressive phenotype associated with the dysregulated production of eicosanoids, in breast, colon, hepatocellular and prostate cancer[1,2,3,4,5,6,7,8]
We demonstrate for the first time that differential transcriptional activity is involved in the regulation of ACSL4 expression in breast cancer cell lines
Deletional analysis revealed that the sequence between −1681 and −873 positions contains at least one negative regulator
Summary
It has been demonstrated that Acyl-CoA synthetase 4 (ACSL4) enzyme expression is elevated in cancer cells, which promotes an aggressive phenotype associated with the dysregulated production of eicosanoids, in breast, colon, hepatocellular and prostate cancer[1,2,3,4,5,6,7,8]. Our group has further established a causal role of ACSL4 expression in the transformation of a non-aggressive phenotype into a highly aggressive one in vitro and in vivo[1,3]. The role of ACSL4 mediating an aggressive phenotype in breast cancer is well accepted, the regulation mechanisms involved in its overexpression in TNBC have not been elucidated yet. We demonstrate that estrogen-related receptor alpha (ERRα) is involved in the transcriptional upregulation of the ACSL4 gene
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