Lactate induced HIF-1α-PRMT1 cross talk affects MHC I expression in monocytes
Lactate induced HIF-1α-PRMT1 cross talk affects MHC I expression in monocytes
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DOI：
10.1016/j.yexcr.2016.08.008
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发表时间：
2016-10-01
影响因子：
3.7
通讯作者：
Sen, Ellora
中科院分区：
文献类型：
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作者：
Gupta, Piyushi;Singh, Ankita;Sen, Ellora
肿瘤浸润单核细胞在肿瘤免疫监测中起着至关重要的作用。由于乳酸盐是肿瘤环境的重要组成部分，我们研究了其在MHC I转录调控中的作用，MHC I对于建立有效的肿瘤免疫应答至关重要。乳酸升高单核细胞MHC I类表达。HLAB表达的增加伴随着HIF-1 α的增加和PRMT1水平的降低。有趣的是，PRMT1和HIF-1 α之间存在互反关系。虽然HIF-1 α抑制降低了乳酸诱导的MHC I，但药物抑制和siRNA介导的PRMT1敲低均上调了HLAB水平。PRMT1过表达挽救乳酸介导的MHC I表达增加。乳酸介导的HLAB启动子核小体占用的变化促进了染色质景观，有利于减少HLAB基因座CRE位点上CREB和PRMT1的募集。PRMT1抑制剂AMI-1在核小体占用和CREB募集方面完全模仿了乳酸对HLAB染色质景观的影响。除了证明乳酸在HLAB转录调控中的重要性外，本研究还首次强调了(i) HIF-1 α -PRMT1调控环的存在以及（ii） PRMT1在调节染色质景观中的作用，这对促进HLAB基因的表达至关重要。(C) 2016 Elsevier Inc.版权所有。
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 HLAB expression was concomitant with increase in HIF-1 alpha and decrease in PRMT1 levels. Interestingly, a reciprocal relationship was observed between PRMT1 and HIF-1 alpha. While HIF-1 alpha inhibition decreased lactate induced MHC I, both pharmacological inhibition and siRNA mediated knockdown of PRMT1 upregulated HLAB levels. PRMT1 over-expression rescued lactate mediated increase in MHC I expression. Lactate mediated changes in nucleosomal occupancy on HLAB promoter facilitated a chromatin landscape that favoured decreased recruitment of CREB and PRMT1 on CRE site of HLAB locus. The effect of lactate on the chromatin landscape of HLAB 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 HLAB, this study highlights for the first time the (i) existence of HIF-1 alpha-PRMT1 regulatory loop and (ii) role of PRMT1 in modulating chromatin landscape crucial for facilitating HLAB gene expression. (C) 2016 Elsevier Inc. All rights reserved.