Coordinated regulation of UGT2B15 expression by long noncoding RNA LINC00574 and hsa-miR-129-5p in HepaRG cells

Recent studies have shown that microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) regulate the expression of drug metabolizing enzymes (DMEs) in human hepatic cells and that a set of DMEs, including UGT2B15, is down-regulated dramatically in liver cells by toxic APAP concentrations. In this study we analyzed mRNA, miRNA, and lncRNA expression profiles in APAP-treated HepaRG cells to explore noncoding RNA-dependent regulation of DME expression. The expression of UGT2B15 and lncRNA LINC00574 was significantly decreased in APAP-treated HepaRG cells. UGT2B15 levels were diminished by LINC00574 suppression using antisense oligonucleotides or small interfering RNA. Furthermore, we found that hsa-miR-129-5p suppressed LINC00574 and decreased UGT2B15 expression via LINC00574 in HepaRG cells. In conclusion, our results indicate that LINC00574 acts as an important regulator of UGT2B15 expression in human hepatic cells, providing experimental evidence and new clues to understand the role of crosstalk between noncoding RNAs. SIGNIFICANCE STATEMENT We showed a molecular network that displays the crosstalk and consequences among mRNA, miRNA, lncRNA and proteins in APAP-treated HepaRG cells. APAP treatment increased the level of hsa-miR-129-5p and decreased that of LINC00574, ultimately decreasing the production of UGT2B15. The proposed regulatory network suppresses UGT2B15 expression through interaction of hsa-miR-129-5p and LINC00574, which may be achieved potentially by recruiting RNA binding proteins.