부산대학교 도서관

Tumor infiltrating monocytes play a crucial role in tumor immune surveillance. As lactate is an important component of the tumor milieu, we investigated its role in the transcriptional regulation of MHC I which is crucial for mounting effective immune responses against tumors. Lactate elevated MHC class I expression in monocytes. Increase in HLA B expression was concomitant with increase in HIF-1α and decrease in PRMT1 levels. Interestingly, a reciprocal relationship was observed between PRMT1 and HIF-1α. While HIF-1α inhibition decreased lactate induced MHC I, both pharmacological inhibition and siRNA mediated knockdown of PRMT1 upregulated HLA B levels. PRMT1 over-expression rescued lactate mediated increase in MHC I expression. Lactate mediated changes in nucleosomal occupancy on HLA B promoter facilitated a chromatin landscape that favoured decreased recruitment of CREB and PRMT1 on CRE site of HLA B locus. The effect of lactate on the chromatin landscape of HLA B was completely mimicked by PRMT1 inhibitor AMI-1 in terms of nucleosomal occupancy and CREB recruitment. Besides demonstrating the importance of lactate in the transcriptional regulation of HLA B , this study highlights for the first time the (i) existence of HIF-1α-PRMT1 regulatory loop and (ii) role of PRMT1 in modulating chromatin landscape crucial for facilitating HLA B gene expression. [ABSTRACT FROM AUTHOR]