Producción CyT
Congreso
Autoría
Fecha
2019
Editorial y Lugar de Edición
Fundación Revista Medicina
Resumen
Información suministrada por el agente en
SIGEVA
Acyl-CoA synthetase 4 (ACSL4) overexpression plays a causal role in the aggressiveness of triple negative breast cancer (TNBC). In turn, a negative correlation has been established between ACSL4 and estrogen receptor alpha (ERα) expression. Our hypothesisis that transcriptional regulation is involved in the differential expression of ACSL4 in breast cancer cells. We observed that TNBC cells(MDA-MB-231 and Hs578T) exhibit greater activity of ACSL4 promoter than ERα+ cell lines(MCF-7 ...
Acyl-CoA synthetase 4 (ACSL4) overexpression plays a causal role in the aggressiveness of triple negative breast cancer (TNBC). In turn, a negative correlation has been established between ACSL4 and estrogen receptor alpha (ERα) expression. Our hypothesisis that transcriptional regulation is involved in the differential expression of ACSL4 in breast cancer cells. We observed that TNBC cells(MDA-MB-231 and Hs578T) exhibit greater activity of ACSL4 promoter than ERα+ cell lines(MCF-7 and T47D) (p<0.001). We described that estrogen-related receptor alpha (ERRα), a transcription factor involved in breast cancer aggressiveness, is involved in ACSL4 expression in TNBC cells. By site directed mutagenesis, we observed that ERRα activates ACSL4 promoter in MDA-MB-231 (p<0.001). ChIP assays showed that ERRα interacts with the ACSL4 promoter in MDA-MB-231 but not in MCF-7 cells (p<0.001). ERRα silencing diminished ACSL4 protein expression (p<0.01), mRNA level (p<0.05) and promoter activity (p<0.001) only in MDA-MB-231. XCT-790, an inverse agonist of ERRα, was able to downregulate ACSL4 expression (p<0.01) on MDA-MB-231 by reducing the transcriptional activity of the promoter (p<0.001). Furthermore, the combination of inhibitors of ACSL4 and ERRα produced a synergistic decrease in MDA-MB-231 cell proliferation (p<0.001). Moreover, ERα restoration in MDA-MB-231 and Hs578T cells reduces ACSL4 promoter activity. This restoration also downregulates ACSL4 protein expression (p<0.01) and mRNA levels (p<0.01). However, the promoter sequence lacks ERα elements and in fact, we did not observe any interaction of ERα and ACSL4 promoter by ChIP analysis on MCF-7 cells. This indirect effect could be produced at least in part by the downregulation that ERα exerts on ERRα expression (p<0.05).The results presented here demonstrate the role of ERRα and ERα in the transcriptional mechanism that leads to different expression of ACSL4 in human breast cancer cells of different aggressiveness.
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Palabras Clave
ERalphaERRalphaTRANSCRIPTIONAL REGULATIONACSL4