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Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer.

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE226589 | GEO | 2023/08/23

REPOSITORIES: GEO

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Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer.

Project description:Colorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/β-catenin and PI3K/AKT pathways. Additionally, the lysine methyltransferase enhancer of zeste homologue 2 (EZH2) is commonly overexpressed in CRC. EZH2 canonically represses gene transcription by trimethylating lysine 27 of histone H3, but also has non-histone substrates. Here, we demonstrated that in CRC, active AKT phosphorylated EZH2 on serine 21. Phosphorylation of EZH2 by AKT induced EZH2 to interact with and methylate β-catenin at lysine 49, which increased β-catenin's binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin to interact with TCF1 and RNA polymerase II and resulted in dramatic gains in genomic regions with β-catenin occupancy. EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC.

| S-EPMC10475482 | biostudies-literature

Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [ChIP-Seq]

Project description:The lysine methyltransferase EZH2 is overexpressed in colorectal cancer (CRC) and has been found to be positively and negatively correlated with CRC patient survival depending on the study suggesting that EZH2 has a complex role in CRC. Here, we demonstrate that AKT-mediated EZH2 S21 phosphorylation induced EZH2 to trimethylate β-catenin at K49, which increased β-catenin’s binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin’s interaction with TCF1 and RNA polymerase II and resulted in a dramatic gain in genomic regions with β-catenin occupancy. Interestingly, EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC. Our results suggest that EZH2 inhibitors have tumor-inhibiting and promoting effects in CRC as they inhibit EZH2-mediated methylation of histone and non-histone targets like β-catenin.

2023-08-23 | GSE226587 | GEO

Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [Cut & Run]

2023-08-23 | GSE226588 | GEO

Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [RNA-Seq]

2023-08-23 | GSE226584 | GEO

Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer.

Project description:Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer.

| PRJNA940741 | ENA

Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [RNA-Seq]

Project description:Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [RNA-Seq]

| PRJNA940739 | ENA

Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [ChIP-Seq]

Project description:Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [ChIP-Seq]

| PRJNA940740 | ENA

Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [Cut & Run]

Project description:Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer. [Cut & Run]

| PRJNA940747 | ENA

Aberrant Activation of β-Catenin Signaling Drives Glioma Tumorigenesis via USP1-Mediated Stabilization of EZH2.

Project description:Aberrant activation of β-catenin signaling is a critical driver for tumorigenesis, but the mechanism underlying this activation is not completely understood. In this study, we demonstrate a critical role of β-catenin signaling in stabilization of enhancer of zeste homolog 2 (EZH2) and control of EZH2-mediated gene repression in oncogenesis. β-Catenin/TCF4 activated the transcription of the deubiquitinase USP1, which then interacted with and deubiquitinated EZH2 directly. USP1-mediated stabilization of EZH2 promoted its recruitment to the promoters of CDKN1B, RUNX3, and HOXA5, resulting in enhanced enrichment of histone H3K27me3 and repression of target gene expression. In human glioma specimens, expression levels of nuclear β-catenin, USP1, and EZH2 correlated with one another. Depletion of β-catenin/USP1/EZH2 repressed glioma cell proliferation in vitro and tumor formation in vivo. Our findings indicate that a β-catenin-USP1-EZH2 axis orchestrates the interplay between dysregulated β-catenin signaling and EZH2-mediated gene epigenetic silencing during glioma tumorigenesis. SIGNIFICANCE: These findings identify the β-catenin-USP1-EZH2 signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.

| S-EPMC9646285 | biostudies-literature

5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation.

Project description:5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.

| S-EPMC7578039 | biostudies-literature

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