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NONO associates with PKM2 and directs histone H3 phosphorylation to promote tumor metastasis (CUT&Tag)

ABSTRACT: Dysregulation of transcriptional programming and epigenome has been identified as fundamental driver of cancer. However, the molecular mechanisms in such processes remain poorly understood. Here, we report that NONO (non-POU domain-containing octamer-binding protein) directly interacts with nuclear PKM2, which is critical for the activation of the NONO-driven transcriptional programme in triple-negative breast cancer (TNBC). We further demonstrate that plasminogen activator inhibitor 1 (PAI1) is a downstream target of NONO/PKM2 complex in TNBC cells through transcriptome analysis. In addition, we show that PKM2-mediated phosphorylation of histone H3 at threonine 11 (H3T11ph) collaborates with acetylation of histone H3 at lysine 27 (H3K27ac), which is due, at least in part, to PKM2 transcriptional activation of TIP60 expression. Importantly, NONO, H3T11ph, and H3K27ac signals are co-enriched at the PAI1 gene loci, which directly boosts PAI transcription. Consistent with above results, we also confirm that the expression of NONO and PKM2 are positively correlated with PAI1 expression in TNBC tissues. Thus, our findings reveal nuclear PKM2 as a novel NONO cofactor required for its biological function and suggest that the NONO/PKM2-PAI1 axis is an attractive therapeutic target in TNBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266179 | GEO | 2025/03/19

REPOSITORIES: GEO

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NONO associates with PKM2 and directs histone H3 phosphorylation to promote tumor metastasis (RNA-Seq)

Project description:Dysregulation of transcriptional programming and epigenome has been identified as fundamental driver of cancer. However, the molecular mechanisms in such processes remain poorly understood. Here, we report that NONO (non-POU domain-containing octamer-binding protein) directly interacts with nuclear PKM2, which is critical for the activation of the NONO-driven transcriptional programme in triple-negative breast cancer (TNBC). We further demonstrate that plasminogen activator inhibitor 1 (PAI1) is a downstream target of NONO/PKM2 complex in TNBC cells through transcriptome analysis. In addition, we show that PKM2-mediated phosphorylation of histone H3 at threonine 11 (H3T11ph) collaborates with acetylation of histone H3 at lysine 27 (H3K27ac), which is due, at least in part, to PKM2 transcriptional activation of TIP60 expression. Importantly, NONO, H3T11ph, and H3K27ac signals are co-enriched at the PAI1 gene loci, which directly boosts PAI transcription. Consistent with above results, we also confirm that the expression of NONO and PKM2 are positively correlated with PAI1 expression in TNBC tissues. Thus, our findings reveal nuclear PKM2 as a novel NONO cofactor required for its biological function and suggest that the NONO/PKM2-PAI1 axis is an attractive therapeutic target in TNBC.

2025-03-19 | GSE266177 | GEO

NONO associates with PKM2 and directs histone H3 phosphorylation to promote tumor metastasis (CUT&Tag)

Project description:NONO associates with PKM2 and directs histone H3 phosphorylation to promote tumor metastasis (CUT&Tag)

| PRJNA1106065 | ENA

NONO associates with PKM2 and directs histone H3 phosphorylation to promote tumor metastasis (RNA-Seq)

Project description:NONO associates with PKM2 and directs histone H3 phosphorylation to promote tumor metastasis (RNA-Seq)

| PRJNA1106066 | ENA

NONO gene expression profile in breast cancer cell

Project description:NONO is one of RNA Binding protein. To investigate the role of NONO in breast cancer cells (TNBC), we carried out microarray.

2020-08-03 | GSE117927 | GEO

Next Generation Sequencing Quantitative Analysis of Wild Type and NONO Knock Down Glioblastoma Cell Line(U251) Transcriptomes

Project description:We identified non-POU domain-containing octamer-binding protein (NONO), a Drosophila behavior human splicing (DBHS) protein, among the most upregulated mRNA splicing factors in glioblastoma multiforme (GBM). NONO was associated with poor prognosis in GBM patients, and overexpression of NONO promoted GBM cell proliferation, invasion and tumorigenesis in a GBM orthotopic xenograft model. Through RNA sequencing based transcriptomic profiling, we found that knockdown of NONO resulted in global changes in alternative splicing-intron retention, and identified GPX1 and CCN1 as two pre-mRNAs targeted by NONO. NONO directly bound to the intron of GPX1 pre-mRNA through the RNA-recognition motifs 2 (RRM2) domain and required interaction with another DBHS protein family member, PSPC1. Knockdown of NONO interfered with redox homeostasis in cells, at least partially, through abnormal splicing of GPX1. Finally, Auranofin, a small-molecule inhibitor targeting NONO, inhibited GBM growth in an orthotopic xenograft model in mice. Taken together, our data revealed that NONO was a key regulator of mRNA splicing in GBM, and that targeting NONO represents a novel and effective therapeutic strategy for the treatment of GBM.

2022-08-03 | GSE190950 | GEO

Next Generation Sequencing Quantitative Analysis of Wild Type and NONO Knock Down Glioblastoma Cell Line (GSC P3) Transcriptomes

2022-08-03 | GSE191021 | GEO

Nono deficiency impedes the proliferation and adhesion of H9c2 cardiomyocytes through Pi3k/Akt signaling pathway [ATAC-seq]

Project description:Purpose: Congenital heart disease (CHD) is the most common type of birth defect and the main noninfectious cause of death during the neonatal stage. Currently, hemizygous loss-of-function variants in NONO(The non-POU domain containing, octamer-binding) gene have been described as the cause of congenital heart defects in males. However, the effects of NONO on cardiac development have not been fully elucidated.

2023-05-01 | GSE211403 | GEO

Nono deficiency impedes the proliferation and adhesion of H9c2 cardiomyocytes through Pi3k/Akt signaling pathway [RNA-seq

2023-05-01 | GSE211401 | GEO

Nucleolar detention of NONO shields DNA double-strand breaks form aberrant transcripts

Project description:RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA–RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.

2024-01-16 | GSE233594 | GEO

O-GlcNAcylation of NONO is Critical for Paraspeckle Component Assembly and Contributes to Tumorigenesis

Project description:Non-POU domain-containing octamer-binding protein (NONO) is a multifunctional member of the Drosophila behavior/human splicing (DBHS) protein family with DNA- and RNA-binding activity. Recent studies revealed that NONO is O-GlcNAcylated and dysregulated in various types of cancer. Excessive O-GlcNAcylation of target proteins has also been implicated in tumorigenesis. However, it is not known whether O-GlcNAcylation of NONO promotes cancer cell growth, and little is known about the effect of O-GlcNAcylation on the biological properties of NONO. This study identifies Thr440 as the primary NONO O-GlcNAcylation site and demonstrates its crucial role in the assembly of paraspeckles, an important subnuclear compartment that facilitates NONO-dependent transcriptional regulation in mammalian cells. We demonstrated that O-GlcNAcylation of NONO is required to maintain the expression of genes related to GO category “microtubule cytoskeleton organization involved in mitosis” and to suppress the expression of genes related to GO category “cellular response to type I interferon”. Moreover, stable depletion of NONO O-GlcNAcylation or NONO knockout significantly inhibited the growth of colon cancer cells. These findings highlight the importance of NONO and its O-GlcNAcylation status in modulating cell cycle progression, immune response, and tumorigenesis.

2024-06-01 | GSE262460 | GEO

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