A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA673187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12936545.fastq.gz | Fastqsanger.gz | |||
| SRR12936546.fastq.gz | Fastqsanger.gz | |||
| SRR12936547.fastq.gz | Fastqsanger.gz | |||
| SRR12936548.fastq.gz | Fastqsanger.gz | |||
| SRR12936549.fastq.gz | Fastqsanger.gz |
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Project description:Long-range oncogenic enhancers play an important role in cancer. Yet, it remains unclear whether similar regulation of tumor suppressor genes is relevant. In this context, loss of expression of the tumor suppressor PTEN is associated with the pathogenesis of various cancers, including T-cell acute lymphoblastic leukemia (T-ALL). Here, we demonstrate that PTEN is regulated in T-cells by a distal enhancer (PE), which is targeted by recurrent focal deletions in T-ALL. This highly conserved regulatory element interacts with and transactivates the PTEN promoter. Consistently, PE deletion in T-ALL cells leads to reduced PTEN levels and proliferative advantage. Moreover, PE-null mice show reduced PTEN levels in the thymus and develop NOTCH1-induced T-ALL with faster kinetics. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by Pten loss. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.
2020-12-17 | GSE160427 | GEO
Project description:Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the PTEN promoter in multiple hematopoietic populations, including T-cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced PTEN levels in T-ALL cells. Moreover, PE-null mice show reduced Pten levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by Pten loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased PTEN levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.
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Project description:Phosphates and tensin homolog (PTEN) is a critical tumor suppressor, and even partial reduction of PTEN levels increases cancer susceptibility. PTEN loss frequently occurs in non-small cell lung carcinoma (NSCLC) and is associated with poor diagnosis. However, there are no effective interventions available to prevent or restore PTEN loss. CREB binding protein (CREBBP or CBP) is a well-known acetyltransferase. PTEN loss in lung cancer carrying CBP loss-of-function (LOF) mutations has not been addressed. Here, we showed that the decreased acetylation of histone deacetylase 3 (HDAC3) due to CBP LOF mutations contributes to PTEN loss in lung cancer. HDAC3 is a member of the class I histone deacetylase family. We found HDAC3 itself is acetylated by CBP at a previously unknown acetylation residue. Our data demonstrated that HDAC3 acetylation is required for gearing down HDAC3 activity and increasing the acetylation of histone proteins to promote the transcription of PTEN. Our findings suggest that HDAC3 acetylation is required for preserving the PTEN expression. The impaired HDAC3 acetylation in CBP LOF mutation lung cancer leads to PTEN loss and consequently promotes tumorigenesis and tumor resistance to chemotherapy. Our findings reveal epigenetic mechanisms of regulating PTEN expression and indicate HDAC3 is a potential target for restoring the tumor suppressor PTEN in CBP LOF mutation cancer.
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Project description:Signal transducer and activator of transcription 3 (STAT3), an important multifunctional regulator of transcription, is expressed in two alternatively spliced isoforms, STAT3α and truncated STAT3β. While STAT3β was postulated to act as a dominant negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful anti-tumorigenic molecule in cancer. Deregulated STAT3 signaling is frequently observed in hematological malignancies, however, the role of STAT3β in acute myeloid leukemia (AML) remains elusive. We analyzed a cohort of AML patients for the STAT3β/α mRNA expression ratio and observed that a higher STAT3β/α ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in leukemia we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in enhanced disease latency in PTEN- and MLL-AF9-dependent mouse models of AML. In conclusion, we demonstrate that STAT3β plays an essential tumor suppressor role in AML and its mRNA expression acts as an important prognostic tool in AML patients.
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Project description:The Forkhead Box, FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown herein, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation A direct comparison of ovarian granulosa cells from wild type d25 and FOXO/PTEN knockout granulosa cell tumors.
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Project description:Hyper-activation of the PI 3-Kinase/ AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, upon partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the co-deletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN-mutant prostate cancer to life-threatening disease. To better assess the role of Phlpp in prostate we performed micorarray analysis of gene expression in the WT and Pten+/-; Phlpp1-/- mice.
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Project description:The loss of apicobasal polarity during the epithelial-to-mesenchymal transition (EMT) is a hall-mark of cancer and metastasis. The key feature of this polarity in epithelial cells is the subdivision of the plasma membrane into apical and basolateral domains, with each orchestrating specific in-tra- and extracellular functions. Epithelial transport and signaling capacities are thought to be determined largely by the quality, quantity and nanoscale organization of proteins residing in these membrane domains, the apicobasal surfaceomes. Despite its implications for cancer, drug uptake and infection, our current knowledge of how the polarized surfaceome is organized and maintained is limited. Here we used chemoproteomic surfaceome scanning to establish proteo-type maps of apicobasal surfaceomes and reveal quantitative distributions of i.a. surface proteas-es, phosphatases and tetraspanins as potential key regulators of polarized cell functionality. We show further that tumor-suppressor PTEN regulates polarized surfaceome architecture and un-cover a potential role in collective cell migration. Our differential surfaceome analysis provides a molecular framework to elucidate polarized protein networks regulating epithelial functions and PTEN-associated cancer progression.
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Project description:PTEN is one of the most frequently mutated tumor suppressor genes, its loss has been reported in multiple tumor types and is associated with a poor outcome. PTEN-L, as a secreted isoform of PTEN, with the ability to enter cells and inhibit tumor cell growth via inhibiting AKT mediated cell proliferation. However, the distinct effect of PTEN-L on PTEN-expression or PTEN-loss tumor cells is not known yet. Here, we identified PTEN-L treatment facilitate E0771-PTEN-null tumor cells, but not PTEN-wide-type tumor cells lung outgrowth. RNA-seq and Western blot analysis suggest PTEN-L stimulation induced PTEN-null tumor cells dormancy, namely, upregulation of dormancy markers p16 and p27, cell cycle arrest, reduced cell proliferation and chemotherapy drugs resistance. Further study suggested PTEN-L mediated p38 signaling activation play the major role for PTEN-null tumor cell dormancy. The p38 inhibitor, SB202190 significantly reversed the PTEN-L induced PTEN-null tumor cells dormancy and outgrowth in lungs. Further investigation indicated the dormant PTEN-null tumor cells could escape from immunosurveillance and thus outgrowth in lungs, as PTEN-L did not promote PTEN-null tumor cells outgrowth in lung of SCID mice. Therefore, we propose that PTEN-L protects PTEN-null tumor cells from immune attack during lung metastasis via activating dormancy related pathways. This study identified PTEN-L as an activator of PTEN-loss tumor cells dormancy, which enables the efficient seeding and outgrowth of tumor cells in metastatic niches. Overall, we highlight PTEN expression status decides the outcome of PTEN-L mediated anti-tumor therapy.
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