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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]

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: GSE227972 | 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 [RNA-seq]

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 | GSE227973 | GEO

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

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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

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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]

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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