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.

Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past

“…Decrease in MHC expression is also evident in cancer cells, which is a mechanism by which they evade the immune response by epigenetically modifying calnexin promoter. But infection with influenza virus in these cancer cells results in enhanced MHC-I presentation due to the increased expression of chromatin remodeling proteins, which stabilizes p53 expression and hence augments the immune surveillance of cancer cells (79). Therefore, molecules that can upregulate chromatin regulators and increase the MHC-I expression could potentially be used for COVID-19.…”

Mechanisms of MHC-I Downregulation and Role in Immunotherapy Response

“…Studies have also revealed that high calnexin expression can promote tumor proliferation and growth in lung cancer ( 113 , 114 ). In both in vitro and an in vivo melanoma models, Scaffold/Matrix- Associated Region-1 (SMAR1) is directly involved in immune evasion mechanisms by positively regulating MHC-I expression through the downregulation of calnexin ( 115 ). Calnexin gene expression was found to be suppressed by the formation of a repression complex that binds to the matrix attachment region (MAR) site on the calnexin promoter.…”

Proteomic Analysis Identifies FNDC1, A1BG, and Antigen Processing Proteins Associated with Tumor Heterogeneity and Malignancy in a Canine Model of Breast Cancer

“…The upregulation of calnexin has been associated with a worse prognosis in several types of cancer, but results are still controversial. Although its increased expression was shown to negatively regulate tumor MHC I surface expression and promote STAT3 oncogene activation leading to tumor malignancy [ 45 , 46 ], calnexin expression levels were significantly higher only in Stage I lung cancer patients when compared to healthy controls, while in colorectal cancer (CRC), no associations were found between higher expressions of calnexin in CRC Stages II or III compared to normal tissue samples [ 47 , 48 ]. Additionally, low or defective expression of calnexin in primary breast cancer was reported to be associated with a higher risk of brain metastases, due to defects in T-cell-based immunosurveillance [ 49 ].…”