Estradiol induces type 8 17beta-hydroxysteroid dehydrogenase expression: crosstalk between estrogen receptor alpha and C/EBPbeta.
Hydroxysteroid (17-beta) dehydrogenase (HSD17B) are the enzymes responsible for the reversible interconversion of 17-hydroxy and 17-keto steroids. The human and mouse type 8 17beta-HSD (HSD17B8) selectively catalyze the conversion of estradiol (E2) to estrone (E1). We previously described thatHSD17B8 is transcriptionally regulated by C/EBPbeta, and that C/EBPbeta is bound to CCAAT boxes located at -5 and -46 of the transcription start site in basal conditions in HepG2 cells. Furthermore, ectopic expression of C/EBPbeta transactivated the HSD17B8 promoter activity. Here, we show that HSD17B8 expression is up-regulated in response to E2 in the estrogen receptor alpha (ERalpha) positive MCF-7 cells. Results showed that this induction is mediated by ERalpha because i) E2 did not induce HSD17B8 expression in ERalphanegative HepG2 cells, ii) ectopic expression of ERalpha restored E2-induced HSD17B8 expression, and iii) this induction was blocked by the anti-ER ICI 182,780. Additional experiments showed that no estrogen response element was necessary for this regulation. However, the CCAAT boxes located at the HSD17B8 proximal promoter were required for E2-induced transcription. Furthermore, co-immunoprecipitation studies revealed tethering of ERalphatoC/EBPbeta in response to E2 in cells expressing ERalpha. Additionally, chromatin immunoprecipitation assays demonstrated that, in response to E2, ERalpha is recruited to the CCAAT boxes in which C/EBPbeta is already bound. Taken together, our results reveal that ERalpha is involved in the transcriptional regulation of HSD17B8 gene in response to E2 through its interaction with C/EBPbeta.
Department of Health Sciences, Universidad Pública de Navarra, Pamplona, Spain.
Mirja
M
Rotinen
Jon
J
Celay
Marta M
MM
Alonso
Aranzazu
A
Arrazola
Ignacio
I
Encio
Joaquin
J
Villar
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D015854:Up-Regulation
D022782:CCAAT-Enhancer-Binding Protein-beta; D047628:Estrogen Receptor alpha; C102228:HSD17B8 protein, human; D011506:Proteins; D004958:Estradiol; D010088:Oxidoreductases