Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2–<i>β</i>-Catenin–BRG1 Transcriptional Network-Driven CD47 Expression

Gowda, Pruthvi; Patrick, Shruti; Singh, Ankita; Sheikh, Touseef; Sen, Ellora

doi:10.1128/mcb.00001-18

Cited by 36 publications

(13 citation statements)

References 55 publications

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“…The reverse effect was observed in the same cells upon the pharmacological elevation of nuclear β-catenin levels. As expected, the CD47 transcriptional downregulation negatively affected the phagocytosis of cancer cells by microglia (158).…”

Section: Impaired Dcs Recruitment: Ccl4 Inhibitionsupporting

confidence: 79%

“…Various transcription factors have been proposed to bind to the promoter of CD47 and explain its upregulated expression in different tumors. Some of them like NF-κB, MYC, SNAI1, ZEB1, HIF-1 and the PKM2-β-catenin-BRG1-TCF4 complex (134,148,157,158) have been implicated in CD47 expression, which strongly suggests that the WNT/β-catenin pathway is involved (Figure 4). Supporting this idea, it has been shown that a constant activation of β-catenin is needed for glioma progression (159), and increased levels of its target genes, such as CD47, have been associated with high-grade GBM (16).…”

Section: Impaired Dcs Recruitment: Ccl4 Inhibitionmentioning

confidence: 99%

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WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

et al. 2019

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WNT/β-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.

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Section: Impaired Dcs Recruitment: Ccl4 Inhibitionsupporting

confidence: 79%

Section: Impaired Dcs Recruitment: Ccl4 Inhibitionmentioning

confidence: 99%

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

et al. 2019

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“…Interestingly, in human breast and lung cancer cell lines, inhibition of the Wnt pathway caused the down modulation of NK cell ligands favoring the evasion from the immune surveillance in this tumor sub-type population [ 219 ]. The contribution of the Wnt pathway to immune evasion is exerted by modulating “marker of self” and “don’t eat me” molecules, such as CD47 [ 220 ], which impair the phagocytic activity of macrophages and dendritic cells [ 221 ]. Furthermore, PD-L1 expression is tightly regulated by the Wnt pathway in triple negative breast cancer [ 222 ].…”

Section: Genetic Mechanisms Of Immune Evasion In Msi Crcmentioning

confidence: 99%

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

Amodio

Mauri

Reilly

et al. 2021

Cancers

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Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.

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“…The immune checkpoint protein CD47 is included in the list of Wnt/β-catenin target molecules with a role in immunity escape. 17 Since β-catenin depletion by siRNA inhibited the expression of CD47 ( Figure 6A), we then sought to know whether erianin regulates the expression of CD47. First, we explored the effects of erianin on CD47 mRNA, protein, and cell surface level.…”

Section: Erianin Decreased Cd47 Expression and Increased Phagocytosismentioning

confidence: 99%

<p>Dual Targeting of Cell Growth and Phagocytosis by Erianin for Human Colorectal Cancer</p>

Sun¹,

Li²,

Zhou³

et al. 2020

DDDT

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Objective: To investigate the effect of erianin on tumor growth and immune response in human colorectal cancer cells (CRC). Methods: The effect of erianin on tumor growth was determined by CCK8 and colony formation assay. Western blotting was used to evaluate the expression levels of relevant proteins and qRT-PCR was used to evaluate the mRNA level of the relevant gene. The transcriptional activity of β-catenin was determined by dual-luciferase reporter assay. Cellular thermal shift assay was used to quantify drug-target interactions. The cell surface CD47 was assessed by flow cytometry. The enrichment of H3K27 acetyl marks on CD47 promoter was evaluated by chromatin immunoprecipitation assay. Phagocytosis assay was used to determine the phagocytic activity of macrophage. In vivo role of erianin was studied on xenograft models. Results: We found that erianin significantly decreased cell survival, colony formation, induced cell cycle arrest, and led to cell apoptosis in SW480 and HCT116 cells. Mechanism analysis demonstrated that erianin inhibited the nuclear translocation and transcriptional activity of β-catenin, which might result from erianin-β-catenin interaction. In addition, the downstream gene expressions, such as c-Myc and cyclin D1, was decreased. More interestingly, erianin decreased the expression of CD47 by regulating H3K27 acetyl marks enrichment on CD47 promoter. Consequently, macrophage-mediated phagocytosis was increased. Our in vivo experiments further confirmed the inhibitory effect of erianin on tumor growth. Conclusion: In summary, erianin could inhibit CRC cells growth and promoted phagocytosis, which suggested erianin as a potential therapeutic strategy for CRC patients.

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Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2–β-Catenin–BRG1 Transcriptional Network-Driven CD47 Expression

Cited by 36 publications

References 55 publications

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

<p>Dual Targeting of Cell Growth and Phagocytosis by Erianin for Human Colorectal Cancer</p>

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