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A single amino acid at the PNT domain of ERG mediates its leukemogenic activity through interaction with the NCoR-HDAC3 co-repressor complex.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE200393 | GEO | 2023/05/26

REPOSITORIES: GEO

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The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG.

Project description:The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3' end of the PNT (pointed) domain, in ERG's ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG's interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention.

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The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

Project description:The ETS transcription factor ERG is involved in several cancers including leukemia. However, ERG domains and co-factors involved in leukemogenesis remain largely uncharacterized and as a transcription factor it is currently undruggable. Here, we report a critical role for the conserved amino-acid proline at position 199, at the 3’ end of the PNT domain, for ERG’s leukemogenic activity. Specifically, we demonstrate that it is required for ERG-induced self-renewal and restriction of myeloid differentiation in hematopoietic progenitor cells and for initiation of leukemia in mouse transduction/transplantation models. Mechanistically, we show that P199 facilitates the interaction of ERG with the NCoR-HDAC3 co-repressor complex. Inhibition of HDAC3 reduced in vitro and in vivo growth of human ERG-dependent leukemic cells as well as growth of ERG dependent prostate cancer cells. Thus, the interaction of ERG with the NCoR-HDAC3 co-repressor complex is required for its oncogenic activity and modulation of this interaction may provide an opportunity for therapeutic intervention.

2023-05-26 | GSE200392 | GEO

The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

2023-05-26 | GSE200391 | GEO

The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

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A single amino acid at the PNT domain of ERG mediates its leukemogenic activity through interaction with the NCoR-HDAC3 co-repressor complex.

Project description:A single amino acid at the PNT domain of ERG mediates its leukemogenic activity through interaction with the NCoR-HDAC3 co-repressor complex.

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RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression.

Project description:The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

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The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

Project description:The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

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The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

Project description:The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

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The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of ERG.

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Nuclear receptor Rev-erbα alleviates intervertebral disc degeneration by recruiting NCoR-HDAC3 co-repressor and inhibiting NLRP3 inflammasome.

Project description:Intervertebral discs (IVDs) are rhythmic tissues that experience daily low-load recovery. Notably, aging and abnormal mechanical stress predispose IVDs to degeneration due to dysrhythmia-induced disordered metabolism. Meanwhile, Rev-erbα acts as a transcriptional repressor in maintaining biorhythms and homeostasis; however, its function in IVD homeostasis and degeneration remains unclear. This study assessed the relationship between low Rev-erbα expression levels and IVD degeneration. Rev-erbα deficiency accelerated needle puncture or aging-induced IVD degeneration, characterized by increased extracellular matrix (ECM) catabolism and nucleus pulposus (NP) cell apoptosis. Mechanistically, Rev-erbα knockdown in NP cells aggravated rhIL1β-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, exacerbating the imbalanced ECM and NP cell apoptosis. Meanwhile, blocking NLRP3 inflammasome activation mitigated Rev-erbα deficiency and needle puncture-induced IVD degeneration. Particularly, Rev-erbα mediated the transcriptional repression of the NLRP3 inflammasome via the ligand heme-binding of nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3) complex. Thus, the increased expression of Rev-erbα in NP cells following short-term rhIL1β treatment failed to inhibit NLRP3 transcription in vitro owing to heme depletion. Pharmacological activation of Rev-erbα in vivo and in vitro alleviated IVD degeneration by altering the NLRP3 inflammasome. Taken together, targeting Rev-erbα may be a potential therapeutic strategy for alleviating IVD degeneration and its related diseases.

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