Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA809413 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18105804.fastq.gz | Fastqsanger.gz | |||
| SRR18105804_1.fastq.gz | Fastqsanger.gz | |||
| SRR18105804_2.fastq.gz | Fastqsanger.gz | |||
| SRR18105805.fastq.gz | Fastqsanger.gz | |||
| SRR18105805_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 72 |
Similar Datasets
Project description:E3 ubiquitin ligases of the Cullin RING Ligase (CRL) family assemble into multiprotein complexes to diversify substrate adaptors and ensure selectivity in substrate engagement for degradation. Here we show a novel mechanism whereby mutations in substrate adaptors can drive neo-substrate degradation in cancer. KBTBD4 is a CRL3 substrate adaptor harbouring recurrent indel mutations in a subset of non-WNT/non-SHH medulloblastomas. We show that these mutations, arising in the substrate recognition domain of KBTBD4, promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. We observe that this neomorphic activity of KBTBD4 mutants induces changes in epigenetic markers and significant alterations in transcription, diverting normal cellular programmes towards increased stemness. These results highlight mutation-driven neomorphic E3 ligase activity as a previously unrecognised mechanism in tumorigenesis, with implications for medulloblastoma pathogenesis and treatment.
2022-10-14 | PXD031683 | Pride
Project description:E3 ubiquitin ligases of the Cullin RING Ligase (CRL) family assemble into multiprotein complexes to diversify substrate adaptors and ensure selectivity in substrate engagement for degradation. Here we show a novel mechanism whereby mutations in substrate adaptors can drive neo-substrate degradation in cancer. KBTBD4 is a CRL3 substrate adaptor harbouring recurrent indel mutations in a subset of non-WNT/non-SHH medulloblastomas. We show that these mutations, arising in the substrate recognition domain of KBTBD4, promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. We observe that this neomorphic activity of KBTBD4 mutants induces changes in epigenetic markers and significant alterations in transcription, diverting normal cellular programmes towards increased stemness. These results highlight mutation-driven neomorphic E3 ligase activity as a previously unrecognised mechanism in tumorigenesis, with implications for medulloblastoma pathogenesis and treatment.
2022-03-30 | GSE197240 | GEO
Project description:Medulloblastoma is the most common malignant brain tumour in children. Genomic studies have identified distinct disease subgroups: wnt/wingless (WNT), sonic hedgehog (SHH), and non-WNT/non-SHH, comprising group 3 and group 4. Alterations in WNT and SHH signalling form the pathogenetic basis for their subgroups, whereas those for non-WNT/non-SHH tumours remain largely elusive. Recent analyses have revealed recurrent in-frame insertions in the E3 ubiquitin ligase adaptor Kelch Repeat and BTB Domain Containing 4 (KBTBD4) in cases of group 3/4 medulloblastoma. Critically, group 3/4 tumours with KBTBD4 mutations typically lack other gene-specific alterations, such as MYC amplification, indicating KBTBD4 insertion mutations as the primary genetic driver. Delineating the role of KBTBD4 mutations thus offers significant opportunities to understand tumour pathogenesis and to exploit the underpinning mechanisms therapeutically. Here, we show a novel mechanism in cancer pathogenesis whereby indel mutations in KBTBD4 drive its recognition of neo-substrates for degradation. We observe that KBTBD4 mutants promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. The degradation of CoREST promoted by KBTBD4 mutation diverts epigenetic programmes inducing significant alterations in transcription to promote increased stemness of cancer cells. Transcriptional analysis of >200 human group 3 and 4 medulloblastomas by RNA-seq, highlights the presence of CoREST and stem-like signatures in tumours with KBTBD4 mutations, which extend to a further sub-set of non-mutant tumours, suggesting CoREST alterations as a novel pathogenetic mechanism of wide relevance in groups 3 and 4. Our findings uncover KBTBD4 mutation as a novel driver of epigenetic reprogramming in non-WNT/non-SHH medulloblastoma, establish a novel mode of tumorigenesis through gain-of-function mutations in ubiquitin ligases (neo-substrate recruitment) and identify both mutant KBTBD4 and CoREST complexes as new druggable targets for improved tumour-specific therapies.
| S-EPMC9525703 | biostudies-literature
Project description:SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here we show that SOX9 is a substrate of FBW7, a tumor suppressor and a SCF (Skp1-Cul1-F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase. Specifically, FBW7-alpha targets T236-phosphorylated SOX9 for ubiquitylation and proteasomal degradation. Further, we demonstrate that FBW7 inactivation stabilizes SOX9 protein promoting migration, metastasis and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. Notably, expression of mutationally stabilized SOX9-T236/240A in medulloblastoma cells coincides with activation of pro-metastatic genes. FBW7 is frequently downregulated in all medulloblastoma subgroups and mutated specifically in SHH-driven medulloblastoma. In cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Finally, pharmacological inhibition of PI3K/Akt/mTOR activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.
2016-09-13 | GSE84320 | GEO
Project description:Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated to date. Here, we evaluate the CoREST repressor complex and the recently developed bivalent inhibitor, corin, within the context of melanoma phenotype plasticity and therapeutic resistance. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin reveals specific effects on histone marks connected to EMT-associated transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin promotes resensitization to BRAFi therapy. DUSP1 is consistently downregulated in BRAFi-resistant melanomas which is reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity can be recapitulated by the p38 MAPK inhibitor, BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAFi- resistant melanoma.
2024-02-01 | GSE156250 | GEO
Project description:Lysine specific demethylase 1 (LSD1/KDM1A) regulates gene expression as part of the CoREST complex, along with co-repressor of REST (CoREST) and histone deacetylase 1 (HDAC1). CoREST is recruited to specific genomic loci by components of the core complex and numerous transient interactions with chromatin associated factors and transcription factors. To sample the chromatin environment in proximity to CoREST, we performed proximity-dependent biotin-identification (BioID) with four different members of the complex in 293T cells. Retaining only targets identified with 3 out of 4 baits, we identified 302 CoREST-associated proteins. Among this group were 16 of 18 known CoREST components and numerous novel associations, including readers (CHD3, 4, 6, 7 and 8), writers (KMT2B and KMT2D) and erasers (KDM2B) of histone methylation. However, components of other HDAC1 containing complexes (e.g. Sin3A, NuRD) were largely absent, suggesting that CoREST functions independently. As LSD1 plays an essential role in early embryonic development, we performed BioID using the endogeneously tagged protein in pluripotent, early- and late-differentiating embryonic stem cells. We identified 157 LSD1-associated proteins of which 66 were constitutively associated across all three time-points (44%), including novel interactions with the MMB and ChAHP complexes. These data imply that the majority of CoREST interactions are dynamic and highly cell type dependent.
2021-11-03 | PXD017344 | Pride
Project description:Using a new model system to track evolution of resistance from ER+ to ER-, we show that the LSD1/CoREST complex is a key determinant for luminal-to-basal reprogramming independently on LSD1’s enzymatic activity.
2022-08-01 | GSE168644 | GEO
Project description:Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated to date. Here, we evaluate the CoREST repressor complex and the recently developed bivalent inhibitor, corin, within the context of melanoma phenotype plasticity and therapeutic resistance. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin reveals specific effects on histone marks connected to EMT-associated transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin promotes resensitization to BRAFi therapy. DUSP1 is consistently downregulated in BRAFi-resistant melanomas which is reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity can be recapitulated by the p38 MAPK inhibitor, BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAFi- resistant melanoma.
2024-02-22 | GSE254701 | GEO
Project description:A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.
2024-01-03 | PXD046091 | Pride