HIF-1–Mediated PPME1 Expression Promotes Breast Cancer Progression via AKT Activation and β-Catenin Recruitment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE314395 | GEO | 2026/06/30
REPOSITORIES: GEO
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Project description:HIF-1–Mediated PPME1 Expression Promotes Breast Cancer Progression via AKT Activation and β-Catenin Recruitment
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Project description:Calreticulin (CALR) is a multi-functional protein that participates in various cellular processes, which include calcium homeostasis, cell adhesion, protein folding and cancer progression. However, the role of CALR in breast cancer is unclear. Here we report that CALR is overexpressed in breast cancer compared with normal tissue, and its expression is correlated with patient mortality and stemness indices. CALR expression was increased in mammosphere cultures, CD24-CD44+ subsets and ALDH+ subsets, which are enriched for breast cancer stem cells (BCSCs). Additionally, CALR knockdown led to BCSC depletion, which impaired tumor initiation and metastasis, and enhanced chemosensitivity in vivo. Chromatinimmunoprecipitation and reporter assays revealed that hypoxia-inducible factor 1 (HIF-1) directly activated CALR transcription in hypoxic breast cancer cells. CALR expression was correlated with Wnt/β-catenin pathway activation and an activator of Wnt/β-catenin signaling abrogated the inhibitory effect of CALR knockdown on mammosphere formation. Taken together, our results demonstrate that CALRfacilitates breast cancer progression by promoting the BCSC phenotype through Wnt/β-catenin signaling in a HIF-1-dependent manner, and suggest that CALR may represent a novel target for breast cancer therapy.
2021-11-16 | GSE181431 | GEO
Project description:Grainyhead-like transcription factor 3 (GRHL3) directs surface ectoderm differentiation under the control of the canonical Wnt/β-catenin pathway. However, the molecular mechanisms that control nuclear GRHL3 expression through β-catenin are not fully understood. Here, we show that the essential for mitotic growth 1 (EMG1) protein constitutes a protein complex with GRHL3, and that EMG1 is required for correct nuclear localization of GRHL3, and for activation of the canonical Wnt signaling pathway. Conditional knockout mutation of Emg1 in the GRHL3-positive surface ectoderm causes neural tube defects at the level of the spinal cord, i.e. spina bifida. Additionally, the severity of compound mutant phenotypes of the Emg1 and Grhl3 genes indicates that they interact genetically in neurulation and palate development. These lines of evidence demonstrate that EMG1 cooperates with GRHL3 in β-catenin–mediated surface ectoderm differentiation. Since the EMG1 mutation causes Bowen-Conradi syndrome and the GRHL3 mutation causes Van der Woude syndrome 2, both of which are associated with neural tube dysplasia and cleft palate, our study will help to better understand the pathogenic mechanisms of these two human genetic diseases.
2025-07-01 | PXD056807 | JPOST Repository
Project description:Medulloblastoma is the most frequent malignant pediatric brain tumor. Considerable efforts are dedicated to identify markers that help to refine treatment strategies. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favorable patient outcome. We report a series of 72 pediatric medulloblastomas evaluated for beta-catenin immunostaining, CTNNB1 mutations, and studied by comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumor cells) in 6 cases and focal nuclear staining (<10% of cells) in 3 cases. The other cases exhibited either a signal strictly limited to the cytoplasm (58 cases) or were negative (5 cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented a strong activation of the Wnt/beta-catenin pathway. Remarkably, 5 out of these 6 tumors showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumors with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2) from diagnosis. All three patients with a focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumors represent a distinct molecular subgroup of medulloblastomas with favorable outcome, indicating that therapy de-escalation should be considered. Yet, international consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. A series of 72 pediatric medulloblastoma tumors has been studied at the genomic level (array-CGH), screened for CTNNB1 mutations and beta-catenin expression (immunohistochemistry). A subset of 40 tumor samples has been analyzed at the RNA expression level (Affymetrix HG U133 Plus 2.0). Correlations between the genomic data, the expression data, the mutational screening, the pathological classification and clinical data is presented in the study. note: aCGH data not submitted to GEO
2009-02-02 | E-GEOD-12992 | biostudies-arrayexpress
Project description:Canonical Wnt/B-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.
2019-01-11 | PXD009305 | Pride
Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation. In vivo liver samples in 4 conditions: Betacat activated (WCE, Tcf4 chipseq, Betacat chipseq, mRNAseq with 2 replicates), Betacat null (WCE, Tcf4 chipseq, mRNAseq with 2 replicates), Betacat control (mRNAseq with 2 replicates), Wild type (mRNAseq with 2 replicates)
2014-01-18 | E-GEOD-35213 | biostudies-arrayexpress
Project description:In most cell types, nuclear β-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of β-catenin but critically depended on GSK3b for effective b-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that b-catenin formed repressive complexes with lymphoid-specific Ikaros and Lef1 factors at the expense of TCF7. While Lef1 was critical for nuclear β-catenin translocation, nuclear b-catenin enabled Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC.
2025-08-08 | GSE245287 | GEO
Project description:Medulloblastoma is the most frequent malignant pediatric brain tumor. Considerable efforts are dedicated to identify markers that help to refine treatment strategies. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favorable patient outcome. We report a series of 72 pediatric medulloblastomas evaluated for beta-catenin immunostaining, CTNNB1 mutations, and studied by comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumor cells) in 6 cases and focal nuclear staining (<10% of cells) in 3 cases. The other cases exhibited either a signal strictly limited to the cytoplasm (58 cases) or were negative (5 cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented a strong activation of the Wnt/beta-catenin pathway. Remarkably, 5 out of these 6 tumors showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumors with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2) from diagnosis. All three patients with a focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumors represent a distinct molecular subgroup of medulloblastomas with favorable outcome, indicating that therapy de-escalation should be considered. Yet, international consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved.
2009-02-02 | GSE12992 | GEO
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 | GSE226584 | GEO
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