Estradiol induces type 8 17β-hydroxysteroid dehydrogenase expression: crosstalk between estrogen receptor α and C/EBPβ

Abstract

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 17β-HSD (HSD17B8) selectively catalyze the conversion ofestradiol (E2) to estrone (E1). We previously described thatHSD17B8 is transcriptionally regulated by C/EBPβ, andthat C/EBPβ 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/EBPβ transactivated the HSD17B8 promoter activity. Here, we show that HSD17B8 expression is up-regulated in response toE2 in the estrogen receptor α (ERα) positive MCF-7 cells. Results showed that this induction is mediated by ERα because i) E2 did not induce HSD17B8 expression in ERαnegative HepG2 cells, ii) ectopic expression of ERα restored E2-induced HSD17B8 expression, and iii) this induction wasblocked 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 ERαtoC/EBPβ inresponse to E2 in cells expressing ERα. Additionally, chromatin immunoprecipitation assays demonstrated that, in response to E2, ERα is recruited to the CCAAT boxes in which C/EBPβ is already bound. Taken together, our results reveal that ERα is involved in the transcriptional regulation ofHSD17B8gene in response to E2 through its interaction with C/EBPβ.