Effect of RCOR2 in cancer cell stemness and immune evasion
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ABSTRACT:
PROVIDER: PRJNA1124878 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the function of RCOR2 in cancer cell stemness and immune evasion, we established RCOR2-KO MDA-MB-231 cells by CRISPR-Cas9. We then performed gene expression profiling analysis using data obtained from RNA-seq of the parental cells as well as two independent KO cell lines. Two biological repeats were applied for each cell line.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and lethal disease. Gasdermins are primarily associated with necrosis via membrane permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. In this study, we report GSDMC upregulation during PDAC progression. GSDMC directly induces genes related to stemness, EMT, and immune evasion. Targeting Gsdmc in murine PDAC models reprograms the immunosupressive tumor microenvironment, resulting in diminished tumor initiation, growth, metastasis, and enhanced response to PD-1 checkpoint inhibition. Mechanistically, we discover that ADAM17 cleaves GSDMC, releasing a C-terminal fragment that translocates to the nucleus and binds to promoter regions of stemness, metastasis, and immune evasion-related genes. Pharmacological inhibition of GSDMC cleavage or hindrance of its nuclear translocation was equally effective in suppressing downstream targets and inhibiting PDAC progression. Our findings position GSDMC as a potential therapeutic target for enhancing treatment response in this deadly disease.
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Project description:Epigenetic regulation of bone formation is a complex network of active proteins and their cofactors. Recent developments in calcified tissue research have revealed several important pathways of epigenetic regulation leading to transcriptional changes in bone cells. Rest Corepressor 2 (Rcor2) is a coregulator of Lysine-specific histone demethylase 1 (Lsd1), a demethylase linked to osteoblast activity, hematopoietic stem cell differentiation and malignancy of different neoplasms. However, the role of Rcor2 in osteoblast differentiation has not yet been examined in detail. We have previously shown that Rcor2 is highly expressed in mesenchymal stromal cells (MSC) and particularly in the osteoblastic lineage. The role of Rcor2 in osteoblastic differentiation in vitro was further characterized and we demonstrate here that lentiviral silencing of Rcor2 in MC3T3-E1 cells led to a decrease in osteoblast differentiation, as shown by decreased alkaline phosphatase and von Kossa stainings as well as by decreased expression of several osteoblast-related marker genes. RNA-sequencing of the Rcor2-downregulated MC3T3-E1 cells revealed decreased repression of Rcor2 target genes, as well as significant upregulation of majority of the differentially expressed genes. While the heterozygous, global loss of Rcor2 in vivo did not lead to a detectable bone phenotype, conditional deletion of Rcor2 in limb-bud mesenchymal cells led to a moderate decrease in cortical bone volume, which was not accentuated by challenging bone formation by ovariectomy or tibial fracture. Furthermore, a global deletion of Rcor2 led to decreased amount of white adipose tissue in vivo and decreased the capacity of primary cells to differentiate into adipocytes in vitro, while the conditional deletion led to decreased adiposity in fracture calluses. Taken together, these results suggest that epigenetic regulation of mesenchymal stromal cell differentiation is mediated by Rcor2, which could thus play an important role in defining the MSC fate.
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Project description:RCOR2 and HDAC1 directly co-binds to CIITA gene. RCOR2 knockout does not affect HDAC1 binding on CIITA gene. RCOR2 has no binding on most MHCII genes.
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Project description:CoREST complexes, composed of LSD1, HDAC1/2, and RCoR1/2/3, are pivotal in neurodevelopment and have long been recognized as transcriptional repressors across various cancers. However, distinct roles of the three RCoR factors remain underexplored. Here, we unveil non-canonical functions of RCoR2 in MYCN-amplified neuroblastoma (NB), underscoring its unique significance compared to its paralogues. This novel insight shifts the paradigm, highlighting RCoR2 as a key determinant of NB chromatin landscape.NB cell growth and tumorigenesis critically depend on RCoR1 and 2, with the RCOR2 gene exhibiting high histone acetylation levels and selective increased expression in NB. Unlike the well-known repressive roles of RCoR1, RNA-seq analyses demonstrate RCoR2 as a positive regulator of gene expression. RCoR2 predominantly occupies active promoters and regions of open chromatin marked by H3K27ac and Pol2, defining its distinct binding pattern compared to RCoR1, which primarily targets enhancers. Surprisingly, CoREST complexes co-occupy chromatin with NB core regulatory transcription factors (CRTFs), which positively drive NB-specific signatures. RCoR2, and not RCoR1, interacts with CRTFs, regulates their expression and its transcription is activated through a strong Super-enhancer. Collectively, these data indicate RCoR2 as a new component of the adrenergic NB core regulatory circuitry (CRC). Mechanistically, H3K27ac and H3K4me2 levels are not drastically altered upon RCoR2 reduction, suggesting RCoR2 is not the primary driver of CoREST complexes’ catalytic activity. Instead, HiChIP data indicate that RCoR2 mediates chromatin looping, facilitating enhancer-promoter interactions and maintaining 3D chromatin architecture to sustain oncogenic transcriptional programs. Taken together, our data underscore RCoR2 as a key oncogenic determinant in neuroblastoma due to its role in chromatin landscape. We propose a model in which RCoR2 facilitates interactions between CRTF-bound enhancers and their associated transcription start sites, thereby sustaining the expression of genes essential for neuroblastoma survival. Consequently, we reveal RCoR2 as a novel critical vulnerability in high-risk neuroblastoma and a promising target for cancer therapeutics.
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Project description:The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor-associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis. A catalytic inhibitor of PRC1 cooperates with immune checkpoint therapy to reverse these processes and suppress metastasis in genetically engineered mouse transplantation models of DNPC. These results reveal that PRC1 coordinates stemness with immune evasion and neoangiogenesis and point to the potential clinical utility of targeting PRC1 in DNPC.
2019-07-18 | GSE103074 | GEO
Project description:The cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of HIV-1 and initiate the antiviral immune response through cGAS–STING–TBK1–IRF3–type I IFN (IFN-I) signaling cascade. HIV-1 uses several strategies to interfere with the host immune molecules and mediate immune evasion. However, the potential role of HIV-1 proteins in cGAS–STING signaling remains unclear. Here we report that the HIV-1 protein p6 suppresses HIV-1-stimulated expression of IFN-I and promotes the immune evasion. Mechanistically, p6 bound with STING and inhibited the activation of STING and the interaction between STING and TBK1. Moreover, the glutamylation of p6 at Glu6 residue inhibited the interaction between STING and TRIM32 or AMFR, which subsequently suppressed the K27- and K63-linked polyubiquitination of STING at Lys337, therefore inhibited STING activation and type I IFN production, while the mutation of Glu6 residue lost the inhibitory effect. However, CoCl2, an agonist for cytosolic carboxypeptidases (CCPs), counteracted the glutamylation of Glu6 residue of p6 and promoted IFN-I production to block the immune evasion of HIV-1. These findings not only reveal a previously unknown mechanism through which an HIV-1 protein mediate immune evasion, but also provide a new therapeutic drug candidate to treat HIV-1 infection.
2021-11-25 | GSE189384 | GEO