SMAR1 favors immunosurveillance of cancer cells by modulating calnexin and MHC I expression.

Abstract

Down-regulation or loss of MHC class I expression is a major mechanism used by cancer cells to evade immunosurveillance and increase their oncogenic potential. MHC I mediated antigen presentation is a complex regulatory process, controlled by antigen processing machinery (APM) dictating immune response. Transcriptional regulation of the APM that can modulate gene expression profile and their correlation to MHC I mediated antigen presentation in cancer cells remain enigmatic. Here, we reveal that Scaffold/Matrix-Associated Region 1- binding protein (SMAR1), positively regulates MHC I surface expression by down-regulating calnexin, an important component of antigen processing machinery (APM) in cancer cells. SMAR1, a bonafide MAR binding protein acts as a transcriptional repressor of several oncogenes. It is down-regulated in higher grades of cancers either through proteasomal degradation or through loss of heterozygosity (LOH) at the Chr.16q24.3 locus where the human homolog of SMAR1 (BANP) has been mapped. It binds to a short MAR region of the calnexin promoter forming a repressor complex in association with GATA2 and HDAC1. A reverse correlation between SMAR1 and calnexin was thus observed in SMAR1-LOH cells and also in tissues from breast cancer patients. To further extrapolate our findings, influenza A (H1N1) virus infection assay was performed. Upon viral infection, the levels of SMAR1 significantly increased resulting in reduced calnexin expression and increased MHC I presentation. Taken together, our observations establish that increased expression of SMAR1 in cancers can positively regulate MHC I surface expression thereby leading to higher chances of tumor regression and elimination of cancer cells.

• Authors: Aftab Alam, Nandaraj Taye, Sonal Patel, Milind Thube, Jayati Mullick, Vibhuti Kumar Shah, Richa Pant, Tanaya Roychowdhury, Nilanjan Banerjee, Subhrangsu Chatterjee, Rittwika Bhattacharya, Rini Roy, Ashis Mukhopadhyay, Devraj Mogare, Samit Chattopadhyay
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 21 Issue 10 Pg. 945-962 (10 2019) ISSN: 1476-5586 [Electronic] United States
• PMID: 31422285 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• BANP protein, human
• Cell Cycle Proteins
• DNA-Binding Proteins
• Histocompatibility Antigens Class I
• Nuclear Proteins
• Proteome
• Calnexin

Topics

• Calnexin (chemistry, genetics, metabolism)
• Cell Cycle Proteins (chemistry, genetics, metabolism)
• Cell Line, Tumor
• DNA-Binding Proteins (chemistry, genetics, metabolism)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Histocompatibility Antigens Class I (chemistry, genetics, metabolism)
• Humans
• Immunologic Surveillance (genetics)
• Influenza A virus
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Nuclear Proteins (chemistry, genetics, metabolism)
• Proteome
• Proteomics (methods)
• Structure-Activity Relationship