PRMT1 Contributes to HNF1A‐AS1‐mediated Regulation Network of CYP3A4 in Huh7 Cells

Abstract

Cytochrome P450 (CYP) 3A4 is an important drug-metabolizing enzyme in human liver. Abnormal activity of CYP3A4 may lead to drug accumulation or over-speed drug clearance in the body, ultimately affecting clinical drug treatment. Huge individual differences in the expression and activity of CYP3A4 have been observed. However, the underlying mechanisms are still elusive. In this study, the molecular mechanism of long non-coding RNA (lncRNA) in the regulation of CYP3A4 has been elucidated. Through lncRNA microarray analysis and quantitative polymerase chain reaction in human liver tissues, we found that HNF1A antisense 1 (HNF1A-AS1), an antisense lncRNA of HNF1A, is positively correlated with the mRNA expression of HNF1A, PXR, and CYP3A4. Gain- and loss-of-function experiments revealed that HNF1A activated the transcription of HNF1A-AS1, and in turn, HNF1A-AS1 affected the stability of HNF1A protein. It is noteworthy that knockdown and overexpression experiments proved that HNF1A-AS1 has a positive regulatory effect on CYP3A4. RNA pull-down followed by mass spectrometry analysis indicated that HNF1A-AS1 interacted with arginine methyltransferase PRMT1 and HNF1A protein in Huh7 cells. Furthermore, the interaction between PRMT1 and PXR was also observed. Therefore, HNF1A-AS1-HNF1A/PXR axis may regulate the expression of CYP3A4 via PRMTI.