Protein kinase A-mediated phosphorylation regulates STAT3 activation and oncogenic EZH2 activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA427214 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6410940.fastq.gz | Fastqsanger.gz | |||
| SRR6410941.fastq.gz | Fastqsanger.gz | |||
| SRR6410942.fastq.gz | Fastqsanger.gz | |||
| SRR6410943.fastq.gz | Fastqsanger.gz | |||
| SRR6410936.fastq.gz | Fastqsanger.gz |
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Project description:The effect of T372E-EZH2 and Wt-EZH2 overexpression on gene expression in TOV112D cells. We found in this study that Protein Kinase A phosphorylates T372-EZH2 and wanted to determine the gene expression changes brought upon this phosphorylation. We made a point mutation (T372E) that mimicked phospho T372-EZH2. The objective was to observe transcriptional changes in TOV112D cells in response to ectopic expression of Wt-EZH2 and T372E-EZH2 point mutation in TOV112D cells.
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Project description:Polycomb repressive complex 2 (PRC2) member enhancer of zeste homolog 2 (EZH2) trimethylates histone H3 lysine 27 (H3K27me3), alters chromatin structure and contributes to epigenetic regulation of gene expression in normal and disease processes. Phosphorylation of EZH2 augmented EZH2 oncogenic activity in cancer but observations have been limited to threonine 350 (T350) and serine 21 (S21) residues by cyclin-dependent kinase 1 and protein kinase B, respectively. In addition, phosphorylation of the evolutionarily conserved T372 motif of EZH2 by p38 resulted in EZH2 interaction with Ying Yang 1 and promoted muscle stem cell differentiation. In the present study, we used epithelial ovarian cancer (OC) cells as a model to demonstrate that phosphorylation of EZH2 at T372 by protein kinase A (PKA) induced a dominant-negative EZH2 phenotype, inhibited OC cell proliferation and migration in vitro and decreased ovarian xenograft tumor growth in vivo. Phosphorylation of T372 by PKA enhanced the interaction between EZH2 and signal transducer and activator of transcription 3 (STAT3), and STAT3 binding to pT372-EZH2 reduced cellular levels of pSTAT3 and downregulated interleukin 6 receptor expression in OC. Furthermore, PKA-mediated pT372-EZH2 decreased ATP levels and altered mitochondrial gene expression, resulting in mitochondrial dysfunction and reduced OC cell growth. These findings demonstrate that PKA-mediated T372 phosphorylation reduces oncogenic EZH2 activity and reveal a novel role for pT372 in regulating EZH2 in OC and possibly other cancers.
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Project description:Our recent work has shown that VprBP is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether VprBP also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that VprBP directly phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, VprBP-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a new mechanism underlying VprBP-driven colonic tumorigenesis by linking VprBP-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.
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Project description:The Polycomb group (PcG) protein enhancer of zeste homolog 2 (EZH2) plays an essential role in histone methylation-mediated epigenetic gene silencing. We demonstrate that under physiological conditions, cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) bind to and phosphorylate EZH2 at threonine 350 (T350) in an evolutionally conserved motif. T350 phosphorylation is required for EZH2 function in silencing of genes that promote differentiation and inhibit proliferation and migration. Blockage of T350 phosphorylation by generating a T350A mutation largely diminishes the global effect of EZH2 on gene silencing. Four experiments have been designed. BJ cells were transfected with si-Control, si-EZH2, si-EZH2 plus RNAi resistant lentivirus expressed EZH2, or si-EZH2 plus RNAi resistant lentivirus expressed T350A mutant for 60 hours. Each experiment was triplicated.
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Project description:Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function
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Project description:Oncogenic EZH2 is overexpressed and extensively involved in the pathophysiology of different cancers including extranodal natural killer/T-cell lymphoma (NKTL). However, the mechanisms regarding EZH2 upregulation is poorly understood, and it still remains untargetable in NKTL. In this study, we examine EZH2 protein turnover in NKTL and identify MELK kinase as a regulator of EZH2 ubiquitination and turnover. Using quantitative mass spectrometry (MS) analysis, we observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. MELK inhibition through both chemical and genetic means led to ubiquitination and destabilization of EZH2 protein. Importantly, we determine that MELK is upregulated in NKTL, and its expression correlates with EZH2 protein expression as determined by tissue microarray derived from NKTL patients. Interestingly, FOXM1, which connected MELK to EZH2 signaling in glioma, was not involved in mediating EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme which deubiquitinates EZH2 at K222. These findings uncover an important role of MELK and USP36 in mediating EZH2 stability in NKTL. Moreover, MELK overexpression led to decreased sensitivity to Bortezomib treatment in NKTL based on deprivation of EZH2 ubiquitination. Therefore, modulation of EZH2 ubiquitination status by targeting MELK may be a new therapeutic strategy for NKTL patients with poor Bortezomib response.
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Project description:The Polycomb group (PcG) protein enhancer of zeste homolog 2 (EZH2) plays an essential role in histone methylation-mediated epigenetic gene silencing. We demonstrate that under physiological conditions, cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) bind to and phosphorylate EZH2 at threonine 350 (T350) in an evolutionally conserved motif. T350 phosphorylation is required for EZH2 function in silencing of genes that promote differentiation and inhibit proliferation and migration. Blockage of T350 phosphorylation by generating a T350A mutation largely diminishes the global effect of EZH2 on gene silencing.
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Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
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Project description:Oral Squamous Cell Carcinoma (OSCC) is a type of cancer that arises from preneoplastic precursors, which undergo genetic and epigenetic modifications. Lysine-specific demethylase 1 (LSD1) is a key OSCC promoter. LSD1 knockout or pharmacological inhibition in mouse OSCC reversed OSCC preneoplasia in our study. LSD1 inhibition attenuated the cell cycle, immunosuppression and promoted the infiltration of CD45+, TCRß+, CD4+, and CD8+ cells. Next, we tested the clinical candidate LSD1 inhibitor (Seclidemstat) in feline clinically spontaneous natural OSCC and found that it was safe and attenuated the STAT3 network. Mechanistic studies have shown that LSD1 reprograms preneoplasia to promote STAT3 signaling, cell cycle mediator CDK7, and immunosuppressive CTLA4 to OSCC progression. Interestingly, we found that the LSD1 inhibitor (SP2509) attenuated cyclin-dependent kinase 7 (CDK7) phosphorylation at T170 and eukaryotic initiation factor 4 B (Eif4B) phosphorylation at S422. We identified a new mechanism in OSCC preneoplasia that LSD1 promotes STAT3 mediated by CDK7 phosphorylation, leading to overall changes in the tumor microenvironment, leading to immunosuppression and progression to OSCC, which could have applications for understanding the mechanism as well as design strategies to control the progression of preneoplasia to OSCC.
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Project description:Oral Squamous Cell Carcinoma (OSCC) is a type of cancer that arises from preneoplastic precursors, which undergo genetic and epigenetic modifications. Lysine-specific demethylase 1 (LSD1) is a key OSCC promoter. LSD1 knockout or pharmacological inhibition in mouse OSCC reversed OSCC preneoplasia in our study. LSD1 inhibition attenuated the cell cycle, immunosuppression and promoted the infiltration of CD45+, TCRß+, CD4+, and CD8+ cells. Next, we tested the clinical candidate LSD1 inhibitor (Seclidemstat) in feline clinically spontaneous natural OSCC and found that it was safe and attenuated the STAT3 network. Mechanistic studies have shown that LSD1 reprograms preneoplasia to promote STAT3 signaling, cell cycle mediator CDK7, and immunosuppressive CTLA4 to OSCC progression. Interestingly, we found that the LSD1 inhibitor (SP2509) attenuated cyclin-dependent kinase 7 (CDK7) phosphorylation at T170 and eukaryotic initiation factor 4 B (Eif4B) phosphorylation at S422. We identified a new mechanism in OSCC preneoplasia that LSD1 promotes STAT3 mediated by CDK7 phosphorylation, leading to overall changes in the tumor microenvironment, leading to immunosuppression and progression to OSCC, which could have applications for understanding the mechanism as well as design strategies to control the progression of preneoplasia to OSCC.
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