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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

2022-07-12 | GSE207794 | GEO

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 [RNA-seq]

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

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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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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.

| S-EPMC6051995 | biostudies-literature

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

Project description:Hypoxia contributes to the progression and metastasis of lung adenocarcinoma (LUAD). However, the specific underlying molecular mechanisms have not been fully elucidated. Here we report that Notch4 is upregulated in lung tissue from lung cancer patients. Functionally, Hypoxia activates the expressions of Delta-like 4 and Notch4, resulting in the excessive proliferation and migration of LUAD cells as well as apoptotic resistance. Notch4 silencing reduced ERK, JNK, and P38 activation. Meanwhile, Notch4 overexpression enhanced ERK, JNK, and P38 activation in LUAD cells. Furthermore, Notch4 exerted pro-proliferation, anti-apoptosis and pro-migration effects on LUAD cells that were partly reversed by the inhibitors of ERK, JNK, and p38. The binding interaction between Notch4 and ERK/JNK/P38 were confirmed by the co-immunoprecipitation assay. In vivo study revealed that Notch4 played a key role in the growth and metastasis of LUAD using two xenograft models. This study demonstrates that hypoxia activates Notch4-ERK/JNK/P38 MAPK signaling pathways to promote LUAD cell progression and metastasis.

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Bulk RNAsequencing of H9 Primed and Naïve Pluripotent Stem Cells with and without EZH2 inhibition.

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2022-03-23 | GSE176172 | GEO

Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [array]

Project description:EZH2 is a H3K27 methylase and a target of cancer epigenetic treatments. We recently reported the oncogenic roles and NTRK1 (TRKA) epigenetic regulation by EZH2 in the MYCN-amplified aggressive neuroblastomas (NB) (L. Here, we investigated the effects and function of small molecule EZH2 inhibitor (EZH2i) on aggressive NB model cell lines. We examined the antitumor effects of EZH2i using WST assay and colony formation assay. By EZH2i treatments, suppression of proliferation, G0/G1 cell cycle arrest, and apoptosis were observed in sensitive NB cells dose-dependently, whereas they were not observed in resistant NB cells. Transcriptome analysis and GSEA indicated significant changes were observed in the gene set related to differentiation and cell cycle arrest in the sensitive cells. We selected genes induced at mRNA level by EZH2i only in the sensitive cells and confirmed tumor suppressor function in NB cells. Almost of the EZH2i-induced gene promoters were marked by H3K27me3 in the sensitive NB cell line. Interestingly, a part of the EZH2i-induced gene promoters have CpG islands and methylated in NB tumor samples registered in databases and the EZH2i-resistant NB cells. Further, combination of EPZ-6438 and 5-aza-deoxycitide, resulted in effective suppression of proliferation in the EPZ-6438-resistant 3 NB cell lines. Transcriptome/methylome analysis of the EPZ-6438 and 5-aza-deoxycitide-treated NB cells revealed the combinational epigenetic regulation of the tumor suppressors and oncogene expression. Finally, we found that methylome analysis of the promoter regions, e.g. VSTM2L, GPNMB, and TIMP3 CpG islands can be biomarkers of EPZ-6438-registancy in unfavorable NB patients. These responsible CpG island methylation appears to be biomarkers for the application of EZH2i/DNMTi combination therapy.

2020-11-25 | GSE162058 | GEO

Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth.

Project description:Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP(+) binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in part to reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells.

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