Abstract:Chromatin architecture and dynamics are regulated by various histone and non-histone proteins. The matrix attachment region binding proteins (MARBPs) play a central role in chromatin organization and function through numerous regulatory proteins. In the present study, we demonstrate that nuclear matrix protein SMAR1 orchestrates global gene regulation as determined by massively parallel ChIP-sequencing. The study revealed that SMAR1 binds to T(C/G) repeat and targets genes involved in diverse biological pathwa… Show more
“…The KM curve for calnexin established that higher expression levels of calnexin correlated with poor prognosis and survival (Figure 6 g ). This observation is in concordance with the fact that breast cancer patients with higher SMAR1 levels show better survival [26], establishing inverse correlation between SMAR1 and calnexin. Therefore, we conclude that SMAR1 expression positively correlates with disease free survival while calnexin is a predictor for poor prognosis and disease outcome.Figure 6Breast cancer patients have high calnexin expression and decreased SMAR1, MHC I expression.…”
Section: Resultssupporting
confidence: 87%
“…SMAR1 is a MAR binding protein and a vital component of the nuclear matrix which controls cellular homeostasis. SMAR1 is known to be down-regulated in various grades of breast cancers [25] and its expression is directly correlated with the survival of patients and disease outcome [26]. Loss of heterozygosity at the SMAR1 loci and Cdc20 mediated proteasomal degradation are main reason behind its dampened expression in cancer cells [12], [13], [14].…”
Section: Resultsmentioning
confidence: 99%
“…During cancer conditions, the tight control of SMAR1 expression gets altered which can provide these transformed cells, the survival advantage. SMAR1 is known to be down-regulated in various grades of breast cancers [25] and its expression is directly correlated with the survival of patients and disease outcome [26]. It is known that SMAR1 gets down-regulated in higher grades of cancer through Cdc20 mediated proteasomal degradation [13], [14].…”
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.
“…The KM curve for calnexin established that higher expression levels of calnexin correlated with poor prognosis and survival (Figure 6 g ). This observation is in concordance with the fact that breast cancer patients with higher SMAR1 levels show better survival [26], establishing inverse correlation between SMAR1 and calnexin. Therefore, we conclude that SMAR1 expression positively correlates with disease free survival while calnexin is a predictor for poor prognosis and disease outcome.Figure 6Breast cancer patients have high calnexin expression and decreased SMAR1, MHC I expression.…”
Section: Resultssupporting
confidence: 87%
“…SMAR1 is a MAR binding protein and a vital component of the nuclear matrix which controls cellular homeostasis. SMAR1 is known to be down-regulated in various grades of breast cancers [25] and its expression is directly correlated with the survival of patients and disease outcome [26]. Loss of heterozygosity at the SMAR1 loci and Cdc20 mediated proteasomal degradation are main reason behind its dampened expression in cancer cells [12], [13], [14].…”
Section: Resultsmentioning
confidence: 99%
“…During cancer conditions, the tight control of SMAR1 expression gets altered which can provide these transformed cells, the survival advantage. SMAR1 is known to be down-regulated in various grades of breast cancers [25] and its expression is directly correlated with the survival of patients and disease outcome [26]. It is known that SMAR1 gets down-regulated in higher grades of cancer through Cdc20 mediated proteasomal degradation [13], [14].…”
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.
“…Notably, miR-222, miR-34a, miR-371a, Bax, Cyclin D1, NFκB, CD40, FN1 and PDGFRB genes showed presence of S/MAR within 1 Kb region upstream to their transcription start sites (TSS). Presence of S/MARs in the promoters of these genes has already been demonstrated experimentally (21,43–49). Further, 35.57% of the total S/MARs were found to be located in the intergenic region (Figure 4A).…”
Scaffold/matrix attachment regions (S/MARs) are DNA elements that serve to compartmentalize the chromatin into structural and functional domains. These elements are involved in control of gene expression which governs the phenotype and also plays role in disease biology. Therefore, genome-wide understanding of these elements holds great therapeutic promise. Several attempts have been made toward identification of S/MARs in genomes of various organisms including human. However, a comprehensive genome-wide map of human S/MARs is yet not available. Toward this objective, ChIP-Seq data of 14 S/MAR binding proteins were analyzed and the binding site coordinates of these proteins were used to prepare a non-redundant S/MAR dataset of human genome. Along with co-ordinate (location) details of S/MARs, the dataset also revealed details of S/MAR features, namely, length, inter-SMAR length (the chromatin loop size), nucleotide repeats, motif abundance, chromosomal distribution and genomic context. S/MARs identified in present study and their subsequent analysis also suggests that these elements act as hotspots for integration of retroviruses. Therefore, these data will help toward better understanding of genome functioning and designing effective anti-viral therapeutics. In order to facilitate user friendly browsing and retrieval of the data obtained in present study, a web interface, MARome (http://bioinfo.net.in/MARome), has been developed.
“…One such protein is SMAR1, a tumor suppressor known to be downregulated in higher grades of cancer and that inhibits β-catenin transcription (121,122). It inhibits βcatenin transcription as well as negatively regulate mir371-373, which is known to target DKK1-an inhibitor of Wnt signaling (121,123,124). Aberrant Wnt signaling or CDC20 mediated degradation, downregulate SMAR1 expression thereby promoting tumorigenesis and cancer progression (125).…”
Wnt signaling is one of the central mechanisms regulating tissue morphogenesis during embryogenesis and repair. The pivot of this signaling cascade is the Wnt ligand, which binds to receptors belonging to the Frizzled family or the ROR1/ROR2 and RYK family. This interaction governs the downstream signaling cascade (canonical/non-canonical), ultimately extending its effect on the cellular cytoskeleton, transcriptional control of proliferation and differentiation, and organelle dynamics. Anomalous Wnt signaling has been associated with several cancers, the most prominent ones being colorectal, breast, lung, oral, cervical, and hematopoietic malignancies. It extends its effect on tumorigenesis by modulating the tumor microenvironment via fine crosstalk between transformed cells and infiltrating immune cells, such as leukocytes. This review is an attempt to highlight the latest developments in the understanding of Wnt signaling in the context of tumors and their microenvironment. A dynamic process known as immunoediting governs the fate of tumor progression based on the correlation of various signaling pathways in the tumor microenvironment and immune cells. Cancer cells also undergo a series of mutations in the tumor suppressor gene, which favors tumorigenesis. Wnt signaling, and its crosstalk with various immune cells, has both negative as well as positive effects on tumor progression. On one hand, it helps in the maintenance and renewal of the leucocytes. On the other hand, it promotes immune tolerance, limiting the antitumor response. Wnt signaling also plays a role in epithelial-mesenchymal transition (EMT), thereby promoting the maintenance of Cancer Stem Cells (CSCs). Furthermore, we have summarized the ongoing strategies used to target aberrant Wnt signaling as a novel therapeutic intervention to combat various cancers and their limitations.
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