Similar Datasets
Project description:Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. The Hippo signaling pathway has emerged as a significant suppressive pathway for hepatocellular carcinogenesis. The core components of the Hippo pathway constitute a kinase cascade, which inhibits the functional activation of YAP/TAZ. Interestingly, the overactivation of YAP/TAZ is commonly observed in hepatocellular carcinoma, although the inhibitory kinase cascade of the Hippo pathway is still functional. Recent studies have indicated that the ubiquitin‒proteasome system also plays important roles in modulating Hippo signaling activity. Our DUB (deubiquitinase) siRNA screen showed that USP1 is a critical regulator of Hippo signaling activity. Analysis of TCGA data demonstrated that USP1 expression is elevated in HCC and associated with poor survival in HCC patients. RNA sequencing analysis revealed that USP1 depletion affects Hippo signaling activity in HCC cell lines. Mechanistic assays revealed that USP1 is required for Hippo/TAZ axis activity and HCC progression. USP1 interacted with the WW domain of TAZ, which subsequently enhanced TAZ stability by suppressing K11-linked polyubiquitination of TAZ. Our study identifies a novel mechanism linking USP1 and TAZ in regulating the Hippo pathway and one possible therapeutic target for HCC.
| S-EPMC10090121 | biostudies-literature
Project description:USP1 modulates hepatocellular carcinoma progression via Hippo/TAZ axis
| PRJNA903373 | ENA
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285628 | GEO
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285627 | GEO
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285630 | GEO
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285629 | GEO
Project description:Gastric cancer is one of the leading causes of cancer-related deaths, and through in vivo and in vitro genetic screens, we identified USP1 as an important factor in promoting tumor progression. Here, we analyzed the transcriptome of sh-USP after knockdown with the aim of identifying downstream effectors of USP1
2024-12-01 | GSE282776 | GEO
Project description:RNA polyadenylation is a key post-transcriptional modification essential for gene expression regulation. However, the role and mechanism of polyadenylation and its key molecule, polyadenylate binding protein nuclear 1 (PABPN1), in hepatocellular carcinoma (HCC) remain poorly understood. This study investigates the role of PABPN1 and its regulatory genes in HCC progression to identify potential therapeutic targets. Analysis of The Cancer Genome Atlas (TCGA) dataset and an independent HCC cohort revealed significant upregulation of PABPN1 in HCC patients, which correlates with poor prognosis. Loss-of-function studies using HCC cell lines and conditional knockout mouse models demonstrated that targeting PABPN1 inhibited HCC progression. Conversely, overexpression of PABPN1 promoted HCC development in vitro and in a hydrodynamic transfection hepatocarcinogenesis mouse model. Mechanistic investigations showed that PABPN1 modulates C5 mRNA polyadenylation and stability, with the PABPN1-C5 axis driving NF-kB activation and recruiting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to promote HCC progression. Therapeutic targeting of the PABPN1-C5 axis using the C5a receptor inhibitor CCX168 significantly inhibited HCC progression in both in vitro and in vivo models. This study identifies PABPN1 as a critical regulator of HCC development and sheds light on the post-transcriptional regulation of complement components in cancer. Targeting the PABPN1-C5 axis represents a promising strategy for HCC treatment.
2025-11-20 | GSE289702 | GEO
Project description:CRISPR Cas9-based functional genomics screening is a powerful approach for identifying and characterizing novel oncology drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacological inhibition of USP1 leads to decreased DNA synthesis concomitant with the induction of S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identified RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as downstream mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition was associated with a reduction in total PCNA protein levels. Ectopic expression of WT and ubiquitin-dead K164R PCNA reversed USP1 inhibitor sensitivity. Our results demonstrate, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to a novel subset of BRCA1/2 WT cancer enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant cell lines and xenograft models. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to post-translational modifications of PCNA. Taken together, USP1 inhibition may represent a unique therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.
2022-09-27 | GSE214121 | GEO
Project description:NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma
| PRJNA1204984 | ENA