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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226584 | GEO | 2023/08/23

REPOSITORIES: GEO

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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

Mouse liver [beta]-catenin chip-seq

Project description:Given that [beta]-catenin is a well-known transcriptional coactivator, and its transcriptional downstream genes may mediate [beta]-catenin’s action on hepatocarcinogenesis. Here, we performed ChIP-seq to study genome-wide distribution of [beta]-catenin in [beta]-catenin[delta](ex3)/+ livers in quest of the putative genes.

2023-02-01 | GSE165853 | GEO

HGPalmer-PDX-NVP-TNKS656

Project description:Strong activation of the oncogenic Wnt/beta-catenin pathway is a main mechanism of resistance to FOXO3a-induced apoptosis promoted by PI3K and AKT inhibitors in colorectal cancer (CRC). Reducing Wnt/beta-catenin activity would sensitize colorectal tumors to these inhibitors. However, no Wnt/beta-catenin signaling inhibitor has proven clinical potential yet. Recently, inhibitors that block tankyrases were shown to reduce colon cancer cell proliferation by decreasing nuclear beta-catenin. We aim to identify determinants of response to these novel Wnt-inhibitors. Therefore, we treated in vivo three different patient-derived xenograft models (PDX; P2, P5 and P30) growing subcutaneously in NOD SCID mice with the novel tankyrase inhibitor NVP-TNKS656.

2015-08-10 | E-MTAB-2446 | biostudies-arrayexpress

β-catenin is a node at orchestrating distinct aspects of epithelial-mesenchymal transition (EMT) and malignant mammary tumor progression

Project description:Canonical Wnt signaling plays crucial roles in the progression of many cancer types. In canonical Wnt signaling, β-catenin acts as a controller determining the transcriptional output: via its N-terminus it recruits the signaling coactivators Bcl9 and Bcl9/9l and via the C-terminus it interacts with the general transcriptional machinery. In the intestine, the C terminal output is essential, while the N-terminus controls only a subset of target genes. In breast cancer, the relative contribution of b-catenin’s different output is not known. Also not known is the functional contribution of β-catenin’s a role in cadherin-mediated cell adhesion, a function which confounds the analysis of conventional loss of function models. To address these unknowns, we combined the MMTV-PyMT mouse model of metastatic breast cancer with mouse lines carrying mutations in β-catenin that abolish its function completely or specifically target the N or C-terminal transcriptional outputs. Notably, the complete lack of β-catenin resulted in apoptosis of mammary tumor cells in vivo and in vitro. In contrast, the loss of β-catenin’s transcriptional functions did not provoke apoptosis but did diminish cell proliferation, epithelial-mesenchymal transition (EMT) and cell migration in vitro. This was also reflected in a reduction in primary tumor growth, tumor invasion, and metastasis formation in vivo. Whole transcriptome analysis identified subsets of genes, which were specifically regulated either by β-catenin’s N or C-terminal activities. Intriguingly, the N-terminal output was critical for TGFb-induced EMT and metastasis formation. The observations from the mouse models correlated with expression studies in human breast cancers.

2020-04-18 | GSE148843 | GEO

Genome-scale CRISPR-Cas9 screen of Wnt/β-catenin signalling identifies therapeutic targets for Colorectal Cancer (ChIP-seq)

Project description:Using genome-scale CRISPR-Cas9 screening, our study revealed KMT2A as a critical regulator of β-catenin-driven CRC progression. To determine the role of KMT2A in β-catenin-mediated transcription, control and KMT2A-ablated DLD1 and SW480 colorectal cancer (CRC) cells were subjected to CHIP-seq analysis using anti-β-catenin and anti-H3K4me3 antibodies. Data obtained from the CHIP-seq experiments indicated a key role of KMT2A in β-catenin binding on active promoters.

2021-05-26 | GSE156081 | GEO

KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer

Project description:Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. However, the molecular mechanisms underlying CRC progression remain to be further defined to improve patient outcomes. In this study, we found that KCTD9, a member of the potassium channel tetramerization domain-containing (KCTD) gene family, was commonly downregulated in CRC tissues and that KCTD9 expression was negatively correlated with the clinical CRC stage. Survival analysis showed that patients whose tumors expressed low KCTD9 levels had poorer outcomes. Functional analyses revealed that KCTD9 overexpression inhibited CRC cell proliferation and metastasis, whereas KCTD9 knockdown promoted CRC cell proliferation and metastasis in both in vitro and in vivo models. Manipulating KCTD9 levels in CRC cells via overexpression or knockdown showed KCTD9 expression positively influenced the degradation of β-catenin levels leading to inhibition of Wnt signaling and reductions in Wnt pathway target gene expression. Mechanistically, we found KCTD9 associated with ZNT9 (Zinc Transporter 9), a coactivator of β-catenin-mediated gene transcription. The overexpression of KCTD9 or knockdown of ZNT9 in CRC cells increased the polyubiquitination and proteasomal degradation of β-catenin. In turn, the KCTD9-ZNT9 interaction disrupted interactions between β-catenin and ZNT9, thereby leading to decreased β-catenin target gene expression and the inhibition of Wnt signaling. In conclusion, our findings propose that KCTD9 functions as a tumor suppressor that inhibits CRC cell proliferation and metastasis by inactivating the Wnt/β-catenin pathway. Moreover, its frequent downregulation in CRC suggests KCTD9 as a potential prognostic and therapeutic target in CRC.

2022-08-19 | GSE205547 | GEO

RNA-sequencing and ChIP-sequencing in murine mesenchymal stem cells treated with Ezh2 inhibitor GSK126 or β-catenin siRNA

Project description:During mesenchymal stem cell (MSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β-catenin is thought to play a critical role in Wnt effects. We show that β-catenin was additive with cytoskeletal signals to prevent adipogenesis, and β-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with β-catenin knockdown enhancing lineage commitment. Chip-seq showed that β-catenin associated with the promoter of EZH2, a key component of the PRC2 complex that governs genome methylation. Knocking down β-catenin lowered EZH2 levels and H3K27me3 at osteogenic loci. Further, when EZH2 was inhibited, β-catenin ’s anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β-catenin effects on MSC to preserve MSC multipotentiality.

2019-10-17 | GSE138980 | GEO

Wnt/β-catenin signaling mediates resistance of colorectal cancer cells to chemoradiotherapy

Project description:Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). Previously, we demonstrated that the Wnt transcription factor, TCF7L2, was overexpressed in primary rectal cancers that were resistant to chemoradiotherapy (CRT), and that TCF7L2 functionally mediates resistance of CRC cells to CRT. However, it remained unclear whether the resistance was mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. We now show that silencing of β-catenin resulted in sensitization of the CRC cell lines LS1034, SW480, and SW837 to CRT, demonstrating a relationship between Wnt/β-catenin signaling and CRT resistance. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiological ligand at the Frizzled receptor, which significantly increased resistance to CRT. This effect could be recapitulated by overexpression of mutated, undegradable β-catenin (S33Y). Again, this resulted in a significantly boosted resistance of RPE-1 cells to CRT, which was abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, we observed higher expression levels of active (unphosphorylated) β-catenin as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation-resistance due to repeated radiation-treatment. Global gene expression profiling identified several altered pathways associated with treatment response as a consequence of Wnt/β-catenin pathway activation, sheading new light on PPARD signaling as a possible mechanism of Wnt mediated resistance. Hence, synergistic pathway inhibition of either Wnt and/or one of the downstream-pathways may represent a promising strategy to increase therapeutic responsiveness to CRT.

2017-05-01 | GSE97543 | GEO

Cell-line-specific gene expression changes following inactivation of the CTNNB1 gene in human colorectal cancer cell lines

Project description:Unrestrained transcriptional activity of β-CATENIN and its binding partner TCF7L2 frequently underlies colorectal tumor initiation and is considered an obligatory oncogenic driver throughout intestinal carcinogenesis. Yet, the TCF7L2 gene carries inactivating mutations in about 10 % of colorectal tumors and is non-essential in colorectal cancer (CRC) cell lines. To determine whether CRC cells acquire TCF7L2-independence through cancer-specific compensation by other T-cell factor (TCF)/lymphoid enhancer‑binding factor (LEF) family members, or rather lose addiction to β-CATENIN/TCF7L2-driven gene expression altogether, we generated multiple CRC cell lines entirely negative for TCF/LEF or β-CATENIN expression. Viability of these cells demonstrates complete β‑CATENIN- and TCF/LEF-independence, albeit one β-CATENIN-deficient cell line eventually became senescent. Absence of TCF/LEF proteins and β-CATENIN consistently impaired CRC cell proliferation, reminiscent of mitogenic effects of WNT/β-CATENIN signaling in the healthy intestine. Despite this common phenotype, β-CATENIN-deficient cells exhibited highly cell-line-specific gene expression changes with little overlap between β-CATENIN- and TCF7L2-dependent transcriptomes. Apparently, β‑CATENIN and TCF7L2 control sizeable fractions of their target genes independently from each other. The observed divergence of β-CATENIN and TCF7L2 transcriptional programs, and the finding that neither β-CATENIN nor TCF/LEF activity is strictly required for CRC cell survival has important implications when evaluating these factors as potential drug targets.

2022-12-13 | GSE199835 | GEO

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