Estradiol induces type 8 17 beta-hydroxysteroid dehydrogenase expression: crosstalk between estrogen receptor alpha and C/EBP beta

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 17 beta-HSD (HSD 17B8) selectively catalyze the conversion of estradiol (E2) to estrone (E1). We previously described that HSD17B8 is transcriptionally regulated by C/EBP beta, and that C/EBP beta 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/EBP beta transactivated the HSD17B8 promoter activity. Here, we show that HSD 17135 expression is up-regulated in response to E2 in the estrogen receptor alpha (ER alpha) positive MCF-7 cells. Results showed that this induction is mediated by ER alpha because i) E2 did not induce HSD17B8 expression in ER alpha negative HepG2 cells, ii) ectopic expression of ERa restored E2-induced HSD17B8 expression, and iii) this induction was blocked by the anti-ER ICI 182780. 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 ER alpha to C/EBP beta in response to E2 in cells expressing ER alpha. Additionally, chromatin immunoprecipitation assays demonstrated that, in response to E2, ERa is recruited to the CCAAT boxes in which C/EBP beta is already bound. Taken together, our results reveal that ER alpha is involved in the transcriptional regulation of HSD17B8 gene in response to E2 through its interaction with C/EBP beta.