Lactate induced HIF-1α-PRMT1 cross talk affects MHC I expression in monocytes.

Abstract

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-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 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-1α-PRMT1 regulatory loop and (ii) role of PRMT1 in modulating chromatin landscape crucial for facilitating HLAB gene expression.

• Authors: Piyushi Gupta, Ankita Singh, Pruthvi Gowda, Sadashib Ghosh, Arpita Chatterjee, Ellora Sen
• Journal: Experimental cell research (Exp Cell Res) Vol. 347 Issue 2 Pg. 293-300 (10 01 2016) ISSN: 1090-2422 [Electronic] United States
• PMID: 27521225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Histocompatibility Antigens Class I
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nucleosomes
• Repressor Proteins
• Lactic Acid
• PRMT1 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Cell Line
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Gene Expression Regulation (drug effects)
• Histocompatibility Antigens Class I (genetics, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Lactic Acid (pharmacology)
• Models, Biological
• Monocytes (drug effects, metabolism)
• Nucleosomes (drug effects, metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding (drug effects)
• Protein-Arginine N-Methyltransferases (antagonists & inhibitors, metabolism)
• Repressor Proteins (antagonists & inhibitors, metabolism)