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EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression [RNA-seq]

ABSTRACT: To investigate the gene expression deregulation in Breast Cancer Tumors treated with P38i, EZH2i, the combination and controls.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207795 | GEO | 2022/07/12

REPOSITORIES: GEO

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EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression [ChIP-seq]

Project description:To investigate the differential abundance of H3k27me3 mark on the promoters of Breast Cancer cells treated with P38i, EPZi, the combination and controls

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EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression.

Project description:Triple-negative breast cancers (TNBCs) are frequently poorly differentiated with high propensity for metastasis. Enhancer of zeste homolog 2 (EZH2) is the lysine methyltransferase of polycomb repressive complex 2 that mediates transcriptional repression in normal cells and in cancer through H3K27me3. However, H3K27me3-independent non-canonical functions of EZH2 are incompletely understood. We reported that EZH2 phosphorylation at T367 by p38α induces TNBC metastasis in an H3K27me3-independent manner. Here, we show that cytosolic EZH2 methylates p38α at lysine 139 and 165 leading to enhanced p38α stability and that p38 methylation and activation require T367 phosphorylation of EZH2. Dual inhibition of EZH2 methyltransferase and p38 kinase activities downregulates pEZH2-T367, H3K27me3, and p-p38 pathways in vivo and reduces TNBC growth and metastasis. These data uncover a cooperation between EZH2 canonical and non-canonical mechanisms and suggest that inhibition of these pathways may be a potential therapeutic strategy.

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EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-07-12 | GSE207796 | GEO

EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression

Project description:EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression

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EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression [ChIP-seq]

Project description:EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression [ChIP-seq]

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EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression [RNA-seq]

Project description:EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression [RNA-seq]

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p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis.

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. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function.

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Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis.

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Project description:Multiple myeloma (MM) is the second most common tumor of the hematologic system. MM remains incurable at this time. In this study, we used bioinformatics analysis to find key genes in the pathogenesis of MM. We first found that Lysosome associated membrane protein 5 (LAMP5) expression was sequentially increased in healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and newly diagnosed MM (NDMM), relapsed MM (RMM). We collected bone marrow from patients with NDMM, HD and post-treatment MM (PTMM) and performed qPCR analysis of LAMP5, and found that the expression of LAMP5 is stronger in NDMM than in HD, and decreases after treatment. Western blotting assay also found more expression of LAMP5 in NDMM than in HD. Patients with high LAMP5 expression have a higher DS (Durie-Salmon) stage and worse prognosis. We next verified the expression of LAMP5 in four MM cell lines and silenced LAMP5 expression in RPMI-8226 and AMO-1, and explored the effects of LAMP5 silencing on MM cell apoptosis and cell cycle by flow cytometry and western blotting. Knockdown of LAMP5 promoted apoptosis in MM cells, but had no effect on the cell cycle. Mechanistically, LAMP5 may exert its pro-tumor effects in MM in part through activation of p38 protein. We screened LAMP5 for the first time as a key gene for MM progression and recurrence, and found that LAMP5 may exert its pro-tumor effects in MM through activation of p38 protein.

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