Similar Datasets
Project description:Neuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets. We identified the histone H2B deubiquitinating enzyme USP44 as the enzyme with the greatest impact on survival in patients with neuroblastoma. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN amplification. The subset of patients with tumors expressing high levels of USP44 had significantly worse survival, including those with tumors lacking MYCN amplification. We showed experimentally that USP44 regulates neuroblastoma cell proliferation, migration, invasion, and neuronal development. Depletion of the histone H2B ubiquitin ligase subunit RNF20 resulted in similar findings, strongly implicating this histone mark as the target of USP44 activity in this disease. Integration of transcriptome and epigenome in analyses demonstrates a distinct set of genes that are regulated by USP44, including those in Hallmark MYC target genes in both murine embryonic fibroblasts and the SH-SY5Y neuroblastoma cell line. We conclude that USP44 is a novel epigenetic regulator that promotes aggressive features and may be a novel target in neuroblastoma. Implications: This study identifies a new genetic marker of aggressive neuroblastoma and identifies the mechanisms by which its overactivity contributes to the pathophysiology of this disease.
| S-EPMC11372370 | biostudies-literature
Project description:Neuroblastoma is an embryonic cancer that disproportionately contributes to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer though epigenetic pathways have been implicated in disease pathogenesis. We performed a computational screen of deubiquitinating enzymes to identify potential new targets and identified the histone H2B deubiquitinating enzyme USP44 as significantly over-expressed in high-risk tumors. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN-amplification. The subset of patients with tumors expressing high levels of USP44 have a significantly worse survival, including those with tumors lacking MYCN-amplification. Depleting USP44 in neuroblastoma cell lines leads to diminished proliferation, migration, invasion, as well as impaired neuritic development in response to retinoic acid. Integrated analysis of RNA-seq and ChIP-seq demonstrates a distinct set of genes that is regulated by USP44, including those in Hallmark pathways critical to tumorigenesis – findings that were completely reversed by the re-introduction of USP44. We conclude that USP44 is a novel epigenetic regulator that restrains differentiation and promotes aggressive features. Our data further suggests that USP44 may be a novel target in this disease.
2024-06-11 | GSE262506 | GEO
Project description:Neuroblastoma is an embryonic cancer that disproportionately contributes to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer though epigenetic pathways have been implicated in disease pathogenesis. We performed a computational screen of deubiquitinating enzymes to identify potential new targets and identified the histone H2B deubiquitinating enzyme USP44 as significantly over-expressed in high-risk tumors. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN-amplification. The subset of patients with tumors expressing high levels of USP44 have a significantly worse survival, including those with tumors lacking MYCN-amplification. Depleting USP44 in neuroblastoma cell lines leads to diminished proliferation, migration, invasion, as well as impaired neuritic development in response to retinoic acid. Integrated analysis of RNA-seq and ChIP-seq demonstrates a distinct set of genes that is regulated by USP44, including those in Hallmark pathways critical to tumorigenesis – findings that were completely reversed by the re-introduction of USP44. We conclude that USP44 is a novel epigenetic regulator that restrains differentiation and promotes aggressive features. Our data further suggests that USP44 may be a novel target in this disease.
2024-06-11 | GSE228131 | GEO
Project description:Neuroblastoma is an embryonic cancer that disproportionately contributes to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer though epigenetic pathways have been implicated in disease pathogenesis. We performed a computational screen of deubiquitinating enzymes to identify potential new targets and identified the histone H2B deubiquitinating enzyme USP44 as significantly over-expressed in high-risk tumors. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN-amplification. The subset of patients with tumors expressing high levels of USP44 have a significantly worse survival, including those with tumors lacking MYCN-amplification. Depleting USP44 in neuroblastoma cell lines leads to diminished proliferation, migration, invasion, as well as impaired neuritic development in response to retinoic acid. Integrated analysis of RNA-seq and ChIP-seq demonstrates a distinct set of genes that is regulated by USP44, including those in Hallmark pathways critical to tumorigenesis – findings that were completely reversed by the re-introduction of USP44. We conclude that USP44 is a novel epigenetic regulator that restrains differentiation and promotes aggressive features. Our data further suggests that USP44 may be a novel target in this disease.
2024-06-11 | GSE228130 | GEO
Project description:USP44 overexpression drives a MYC-like gene expression program in neuroblastoma through epigenetic reprogramming
| PRJNA948367 | ENA
Project description:USP44 overexpression drives a MYC-like gene expression program in neuroblastoma through epigenetic reprogramming
| PRJNA948370 | ENA
Project description:USP44 overexpression drives a MYC-like gene expression program in neuroblastoma through epigenetic reprogramming
| PRJNA948371 | ENA
Project description:USP44 overexpression drives a MYC-like gene expression program in neuroblastoma through epigenetic reprogramming
| PRJNA1092084 | ENA
Project description:Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration resistant prostate cancers become androgen receptor (AR) signaling-independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome and interactome using in vivo, in vitro and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR-co-factors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for EZH2 inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights on how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage-specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.
| S-EPMC6715370 | biostudies-literature
Project description:Pituitary adenomas are common, benign brain tumors. Some tumors show aggressive phenotypes including early recurrence, local invasion and distant metastasis, but the underlying mechanism to drive the progression of pituitary tumors has remained to be clarified. Aerobic glycolysis known as the Warburg effect is one of the emerging hallmarks of cancer, which has an impact on the tumor biology partly through epigenetic regulation of the tumor-promoting genes. Here, we demonstrate metabolic reprogramming in pituitary tumors contributes to tumor cell growth with epigenetic changes such as histone acetylation. Notably, a shift in histone acetylation increases the expression of telomerase reverse transcriptase (TERT) oncogene, which drives metabolism-dependent cell proliferation in pituitary tumors. These indicate that epigenetic changes could be the specific biomarker for predicting the behavior of pituitary tumors and exploitable as a novel target for the aggressive types of the pituitary tumors.
| S-EPMC8275863 | biostudies-literature