Noncanonical PRC1.1 Targets BTG2 to Retain Cyclin Gene Expression and Cell Growth in Neuroblastoma [microarray]
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PROVIDER: PRJNA1244139 | ENA |
REPOSITORIES: ENA
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Project description:Noncanonical PRC1.1 Targets BTG2 to Retain Cyclin Gene Expression and Cell Growth in Neuroblastoma
| PRJNA1242967 | ENA
Project description:Cancer cells exploit epigenetic modifications and post-transcriptional regulations to form oncogenic gene expression networks. However, how these machineries collaboratively orchestrate malignancy remains elusive. One of aberrant epigenetic pathways in cancer is Polycomb repressive complex 1 (PRC)-mediated H2AK119 monoubiquitination (H2AK119ub1) with subsequent silencing of tumor suppressor genes. Despite previous efforts, the biological and clinical significance of PRC1 remains unclear in neuroblastoma (NB), an aggressive sympathoadrenal solid tumor in children. In this study, we demonstrated that knockdown of RING1A, one of the E3 ubiquitin ligases of PRC1, reduced cell viability and enrichment of H2AK119ub1 in NB cells. Transcriptional profiling revealed RING1A-specific targets, whose lower expression was associated with poor outcomes in NB patients. Among these genes, BTG2, a component of the CCR4-NOT polyA deadenylase complex, harbored a hypomethylated CpG island occupied by H2AK119ub1 and accessory proteins of noncanonical PRC1.1 (ncPRC1.1). Biological experiments uncovered that BTG2 suppressed NB cell growth in vitro and inhibited tumor formation in vivo. Moreover, BTG2 perturbed cell cycle progression and selectively destabilized the mRNAs of the cyclin genes CCNA2, CCNB1, and CCNB2. In NB patient cohorts, lower expression of BTG2 was associated with poor outcomes and inversely correlated with those cyclin gene expression. Collectively, we have uncovered a crosstalk between epigenetic modifications and post-transcriptional regulations, in which ncPRC1.1-mediated silencing of BTG2 retains cyclin gene expression and cell proliferation in NB. This study provides new insights into how epigenetic pathways contribute to NB malignancy.
2026-04-02 | GSE293156 | GEO
Project description:To explore the common and specific targets of RING1A and RING1B, we conducted microarray analyses on NGP and SK-N-BE cells transduced with shRING1, shRNF2, or their combination.
2025-06-16 | GSE293336 | GEO
Project description:In addition to lipid second messengers derived from the plasma membrane, increasing evidence supports the existence of nuclear lipid-dependent signaling networks. Diacylglycerol is a key second messenger, generated at the nuclear level, which is metabolized by diacylglycerol kinases (DGKs). It has been demonstrated that nuclear DGK-ζ negatively regulates cell cycle progression. The aim of this study was to identify key determinants of nuclear DGK-ζ-dependent cell cycle arrest in C2C12 mouse myoblasts. Using DNA microarrays, Real-Time RT-PCR and western blot, we demonstrated that nuclear DGK-ζ downregulated the expression of cyclin D1 and increased the expression of TIS21/BTG2/PC3, a transcriptional regulator of cyclin D1 with a strong anti-proliferative function. Overexpression of TIS21/BTG2/PC3 blocked the cells in G1 phase of the cell cycle and decreased the levels of Ser807/811 phosphorylated retinoblastoma protein, similarly to overexpression of DGK-ζ. Moreover, during myogenic differentiation of C2C12 cells, we showed an increase of TIS21/BTG2/PC3 expression and a decrease in cyclin D1 levels. siRNA downregulation of TIS21/BTG2/PC3 impaired myogenic differentiation by opposing cell cycle arrest. In summary, these data identify TIS21/BTG2/PC3 and cyclin D1 as downstream effectors of the nuclear DGK-ζ and highlight the importance of this DGK isoform in the regulation of myoblast proliferation and differentiation.
2009-09-30 | GSE11770 | GEO
Project description:Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during tissue development. To identify protein complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease.
2026-02-26 | GSE316009 | GEO
Project description:Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during tissue development. To identify protein complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease.
2026-02-26 | GSE307920 | GEO
Project description:Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during tissue development. To identify protein complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease.
2026-02-26 | GSE307922 | GEO
Project description:Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during tissue development. To identify protein complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease.
2026-02-26 | GSE315996 | GEO
Project description:Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during tissue development. To identify protein complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease.
2026-02-26 | GSE315997 | GEO
Project description:Destabilization of the noncanonical PRC1.1 complex via USP7 inhibition induces neuronal differentiation in neuroblastoma
| PRJNA1400450 | ENA