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MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [RNA-seq]

ABSTRACT: Activation of YAP is frequently observed in cancer and is associated with poor outcomes, making it an attractive target for therapeutic intervention. Previous studies have mainly focused on blocking the interaction of YAP with TEAD transcription factors. Here we took a different approach by interfering with the binding of YAP to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. We found that expression of MY-COMP inhibited the binding of B-MYB to YAP, resulting in growth defects, nuclear abnormalities and polyploidization in HeLa cells. Additionally, MY-COMP interfered with normal cell cycle progression of YAP-dependent uveal melanoma cells, but its effects were much weaker in YAP-independent cutaneous melanoma cell lines. MY-COMP antagonized the YAP-dependent expression of MMB-regulated cell cycle genes, providing an explanation for the observed phenotypes. We identified NIMA-related kinase (NEK2) as a candidate target downstream of YAP and B-MYB, contributing to the transformation of YAP-dependent uveal tumor cell lines. Overall, our findings suggest that targeting selected YAP-MMB regulated genes such as NEK2 or inhibiting the WW-domains of YAP to suppress YAP-regulated cell cycle genes could provide a novel mechanism to antagonize the pro-tumorigenic functions of YAP.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227973 | GEO | 2024/03/06

REPOSITORIES: GEO

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MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [CUT&RUN]

Project description:Activation of YAP is frequently observed in cancer and is associated with poor outcomes, making it an attractive target for therapeutic intervention. Previous studies have mainly focused on blocking the interaction of YAP with TEAD transcription factors. Here we took a different approach by interfering with the binding of YAP to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. We found that expression of MY-COMP inhibited the binding of B-MYB to YAP, resulting in growth defects, nuclear abnormalities and polyploidization in HeLa cells. Additionally, MY-COMP interfered with normal cell cycle progression of YAP-dependent uveal melanoma cells, but its effects were much weaker in YAP-independent cutaneous melanoma cell lines. MY-COMP antagonized the YAP-dependent expression of MMB-regulated cell cycle genes, providing an explanation for the observed phenotypes. We identified NIMA-related kinase (NEK2) as a candidate target downstream of YAP and B-MYB, contributing to the transformation of YAP-dependent uveal tumor cell lines. Overall, our findings suggest that targeting selected YAP-MMB regulated genes such as NEK2 or inhibiting the WW-domains of YAP to suppress YAP-regulated cell cycle genes could provide a novel mechanism to antagonize the pro-tumorigenic functions of YAP.

2024-03-06 | GSE227972 | GEO

The MybMuvB complex is required for YAP dependent transcription of mitotic genes

Project description:YAP/TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin-association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes co-activated by YAP and B-MYB is associated with poor survival of cancer patients. Together, our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways.

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MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells

Project description:MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells

| PRJNA947598 | ENA

MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [RNA-seq]

Project description:MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [RNA-seq]

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MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [CUT&RUN]

Project description:MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [CUT&RUN]

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Interaction of YAP1 with the Myb-MuvB (MMB) complex sustain proliferation in the postnatal heart

Project description:YAP, a major downstream effector of the Hippo signaling pathway, is an important regulator of cell proliferation. Previous studies have shown that YAP cooperates with the two transcription factors E2F and MYC to mediate G1 to S transition by regulating early cell cycle gene expression. On the other hand, the ability of YAP to regulate G2/M gene expression is dependent on the Myb-MuvB (MMB) complex, consisting of the evolutionary MuvB core complex of five proteins and the facultative subunit B-MYB, a transcription factor. We now carried out interaction studies and found that YAP directly binds to the B-MYB subunit of MMB. Disruption of the YAP/B-MYB interaction by overexpression of the YAP binding domain of B-MYB results in errors in cell division. We also show that YAP and MMB interact in vivo in the developing heart. Genome wide expression and binding studies revealed that YAP and MMB regulate an overlapping set of cell cycle genes in cardiomyocytes. Cardiac specific deletion of the LIN9 subunit of MMB prevents the upregulation of cell cycle genes and the increased proliferation of cardiomyocytes lacking the hippo-signaling component SAV1. Similarly, we find that proliferation of postnatal cardiomyocytes induced by constitutive active YAP depends on MMB. Our findings provide new insights in the mechanisms of cell cycle regulation by the Hippo pathway in cardiomyocytes and suggests that YAP and MMB interact to induce genes critical for cell cycle regulation.

2020-05-07 | GSE137132 | GEO

Oncogenic YAP mediates changes in chromatin accessibility and activity that drive cell cycle gene expression and cell migration

Project description:YAP, the key protein effector of the Hippo pathway, is a transcriptional co-activator that controls the expression of cell cycle genes, promotes cell growth and proliferation and regulates organ size. YAP modulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers remain poorly understood. Here we show that constitutive active YAP5SA leads to widespread changes in chromatin accessibility in untransformed MCF10A cells. Newly accessible regions include YAP-bound enhancers that mediate activation of cycle genes regulated by the Myb-MuvB (MMB) complex. By CRISPR-interference we identify a role for YAP-bound enhancers in phosphorylation of Pol II at Ser5 at MMB-regulated promoters, extending previously published studies that suggested YAP primarily regulates the pause-release step and transcriptional elongation. YAP5SA also leads to less accessible 'closed' chromatin regions, which are not directly YAP-bound but which contain binding motifs for the p53 family of transcription factors. Diminished accessibility at these regions is, at least in part, a consequence of reduced expression and chromatin-binding of the p53 family member ΔNp63 resulting in downregulation of ΔNp63-target genes and promoting YAP-mediated cell migration. In summary, our studies uncover changes in chromatin accessibility and activity that contribute to the oncogenic activities of YAP.

2023-02-15 | GSE193704 | GEO

HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.

2020-05-26 | PXD013988 | Pride

Transcription profiling of Drosophila Myb-MuvB/dREAM

Project description:Myb-MuvB (MMB)/dREAM is a nine subunit complex first described in Drosophila as a repressor of transcription, dependent upon E2F2 and the RBFs. Myb, an integral member of MMB, curiously plays no role in the silencing of the test genes previously analyzed. Moreover, Myb plays an activating role in DNA replication in Drosophila egg chamber follicle cells. The essential functions for Myb are executed as part of MMB. This duality of function lead to the hypothesis that MMB, which contains both known activator and repressor proteins, might function as part of a switching mechanism that is dependent upon DNA sites and developmental context. Here, we used proliferating Drosophila Kc tissue culture cells to explore both the network of genes regulated by MMB (employing RNAi and micro-array expression analysis) and the genomic locations of MMB following chromatin immunoprecipitation (ChIP) and tiling array analysis. MMB occupies thousands of chromosomal sites where a substantial number are proximal to repressed genes that are normally expressed in a wide range of developmental pathways. At many of these sites, E2F2 was critical for repression whereas at other non-overlapping sites, Myb was critical for repression. These data highlight that the MMB factors are utilized in a combinatorial way for targeting gene regulation. We also found sites where MMB was a positive regulator of transcript levels that included genes required for mitotic functions (G2/M), which may explain some of the chromosome instability phenotypes attributed to loss of Myb function in myb mutants. Experiment Overall Design: RNAi to deplete Lin-52, Mip40, Myb, Mip120, Mip130, E2F2, both RBFs (RBF1 and RBF2) and L(3)MBT were performed in triplicate. RNAi with a nonspecific RNA derived from a pBSK+ plasmid (named SK+) was used as control. Total RNA was extracted from RNAi-transfected cells after 4 days using RNeasy Mini Kit (QIAGEN).

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