Estrogen-related receptor ERRα-mediated downregulation of human hydroxysteroid sulfotransferase (SULT2A1) in Hep G2 cells.

Hydroxysteroid sulfotransferase SULT2A1 catalyzes the sulfation of hydroxysteroids and xenobiotics. It plays an important role in the detoxification of hydroxyl-containing xenobiotics and in the regulation of the biological activities of hydroxysteroids. ERRα is an orphan member of the nuclear receptor superfamily that is closely related to estrogen receptor alpha (ERα). Here we report that the mRNA expression of human SULT2A1 was suppressed by ERRα in Hep G2 cells. To investigate the mechanisms of this regulation, the effects of ERRα on human SULT2A1 promoter transcription in Hep G2 cells were investigated. Reporter luciferase assay results showed that ERRα significantly represses human SULT2A1 promoter transcription in Hep G2 cells. Deletion analysis indicated that human SULT2A1 promoter region between positions -188 and -130 is necessary for its repression by ERRα in Hep G2 cells. The 5' DNA -188 to -130 region of human SULT2A1 contains IR2 and DR4 hormone response elements and two putative ERRα response elements (ERREs) (ERRE188: GCAAGCTCA and ERRE155: ATAAGTTCA). Interestingly, ERRE188 overlaps with the IR2 element and ERRE155 overlaps with the DR4 element. Our further investigation demonstrated that ERRα represses human SULT2A1 promoter transcription by competing with other nuclear receptors for binding to IR2 or DR4 elements. The interaction of ERRE188 and ERRE155 elements with ERRα was confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis. Our results suggest that ERRα may play an important role in regulating the metabolism of drugs and xenobiotics and in regulating endogenous hydroxysteroid activities via the regulation of SULT2A1.