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A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia.

ABSTRACT: 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.

SUBMITTER: Tottone L

PROVIDER: S-EPMC7810363 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia

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

A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia

Project description:A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia

| PRJNA673187 | ENA

In renal cell carcinoma the PTEN splice variant PTEN-? shows similar function as the tumor suppressor PTEN itself.

Project description:BackgroundLoss of PTEN is involved in tumor progression of several tumor entities including renal cell carcinoma (RCC). During the translation process PTEN generates a number of splice variants, including PTEN-?. We analyzed the impact of PTEN-? in RCC progression.MethodsIn specimens of RCC patients the expression of PTEN-? and PTEN was quantified. The PTEN expressing RCC cell line A498 and the PTEN deficient 786-O cell line were stably transfected with the PTEN-? or PTEN transcript. In Caki-1 cells that highly express PTEN-?, this isoform was knocked down by siRNA. Cell migration, adhesion, apoptosis and signaling pathways activities were consequently analyzed in vitro.ResultsPatients with a higher PTEN-? expression had a longer lymph node metastasis free and overall survival. In RCC specimens, the PTEN-? expression correlated with the PTEN expression. PTEN-? as well as PTEN induced a reduced migration when using extracellular matrix (ECM) compounds as chemotaxins. This effect was confirmed by knockdown of PTEN-?, inducing an enhanced migration. Likewise a decreased adhesion on these ECM components could be shown in PTEN-? and PTEN transfected cells. The apoptosis rate was slightly increased by PTEN-?. In a phospho-kinase array and Western blot analyses a consequently reduced activity of AKT, p38 and JNK could be shown.ConclusionsWe could show that the PTEN splice variant PTEN-? acts similar to PTEN in a tumor suppressive manner, suggesting synergistic effects of the two isoforms. The impact of PTEN-? in context of tumor progression should thus be taken into account when generating new therapeutic options targeting PTEN signaling in RCC.

| S-EPMC6025732 | biostudies-literature

The PTEN Tumor Suppressor Forms Homodimers in Solution.

Project description:As the phosphoinositol-3-kinase antagonist in the PI3K pathway, the PTEN tumor suppressor exerts phosphatase activity on diacylphosphatidylinositol triphosphate in the plasma membrane. Even partial loss of this activity enhances tumorigenesis, but a mechanistic basis for this aspect of PTEN physiology has not yet been established. It was recently proposed that PTEN mutations have dominant-negative effects in cancer via PTEN dimers. We show that PTEN forms homodimers in vitro, and determine a structural model of the complex from SAXS and Rosetta docking studies. Our findings shed new light on the cellular control mechanism of PTEN activity. Phosphorylation of the unstructured C-terminal tail of PTEN reduces PTEN activity, and this result was interpreted as a blockage of the PTEN membrane binding interface through this tail. The results presented here instead suggest that the C-terminal tail functions in stabilizing the homodimer, and that tail phosphorylation interferes with this stabilization.

| S-EPMC4598300 | biostudies-literature

Regulation of the tumor suppressor PTEN by SUMO.

Project description:The crucial function of the PTEN tumor suppressor in multiple cellular processes suggests that its activity must be tightly controlled. Both, membrane association and a variety of post-translational modifications, such as acetylation, phosphorylation, and mono- and polyubiquitination, have been reported to regulate PTEN activity. Here, we demonstrated that PTEN is also post-translationally modified by the small ubiquitin-like proteins, small ubiquitin-related modifier 1 (SUMO1) and SUMO2. We identified lysine residue 266 and the major monoubiquitination site 289, both located within the C2 domain required for PTEN membrane association, as SUMO acceptors in PTEN. We demonstrated the existence of a crosstalk between PTEN SUMOylation and ubiquitination, with PTEN-SUMO1 showing a reduced capacity to form covalent interactions with monoubiquitin and accumulation of PTEN-SUMO2 conjugates after inhibition of the proteasome. Moreover, we found that virus infection induces PTEN SUMOylation and favors PTEN localization at the cell membrane. Finally, we demonstrated that SUMOylation contributes to the control of virus infection by PTEN.

| S-EPMC3461367 | biostudies-literature

Tumor suppressor PTEN is a physiologic suppressor of chemoattractant-mediated neutrophil functions.

Project description:The recruitment and activation of neutrophils at infected tissues is essential for host defense against invading microorganisms. However, excessive neutrophil recruitment or activation can also damage the surrounding tissues and cause unwanted inflammation. Hence, the responsiveness of neutrophils needs to be tightly regulated. In this study, we have investigated the functional role of tumor suppressor PTEN in neutrophils by using a mouse line in which PTEN is disrupted only in myeloid-derived cells. Chemoattractant-stimulated PTEN(-/-) neutrophils displayed significantly higher Akt phosphorylation and actin polymerization. A larger fraction of these neutrophils displayed membrane ruffles in response to chemoattractant stimulation. In addition, chemoattractant-induced transwell migration and superoxide production were also augmented. Single-cell chemotaxis assays showed that PTEN(-/-) neutrophils have a small (yet statistically significant) defect in directionality. However, these neutrophils also showed an increase in cell speed. As a result, overall chemotaxis, which depends on speed and directionality, was not affected. Consistent with the increased responsiveness of PTEN(-/-) neutrophils, the in vivo recruitment of these cells to the inflamed peritoneal cavity was significantly enhanced. Thus, as a physiologic-negative regulator, PTEN should be a promising therapeutic target for modulating neutrophil functions in various infectious and inflammatory diseases.

| S-EPMC1874585 | biostudies-literature

Disentangling PTEN-cooperating tumor suppressor gene networks in cancer.

Project description:We have recently performed a whole-body, genome-wide screen in mice using a single-copy inactivating transposon for the identification of Pten (phosphatase and tensin homolog)-cooperating tumor suppressor genes (TSGs). We identified known and putative TSGs in multiple cancer types and validated the functional and clinical relevance of several promising candidates for human prostate cancer.

| S-EPMC5540202 | biostudies-literature

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure.

Project description:The tumor suppressor, PTEN, is one of the most commonly mutated genes in cancer. Recently, PTEN has been shown to localize in the nucleus and is required to maintain genomic stability. Here, we show that nuclear PTEN, independent of its phosphatase activity, is essential for maintaining heterochromatin structure. Depletion of PTEN leads to loss of heterochromatic foci, decreased chromatin compaction, overexpression of heterochromatic genes, and reduced protein stability of heterochromatin protein 1 ?. We found that the C-terminus of PTEN is required to maintain heterochromatin structure. Additionally, cancer-associated PTEN mutants lost their tumor-suppressor function when their heterochromatin structure was compromised. We propose that this novel role of PTEN accounts for its function in guarding genomic stability and suppressing tumor development.

| S-EPMC4614552 | biostudies-literature

Circling back to PTEN: Fumarate inhibits canonical tumor suppressor.

Project description:Ge et al. (2022) describes an inhibitory, post-translational modification of PTEN at C211 by fumarate, which offers new insight into the integration of PI3K signaling and metabolism via a potential feedforward regulatory mechanism involving a PI3K-glucose-fumarate-PTEN axis.

| S-EPMC10311992 | biostudies-literature

Engineering ePTEN, an enhanced PTEN with increased tumor suppressor activities.

Project description:The signaling lipid phosphatidylinositol (3,4,5)-trisphosphate (PIP3) is a key regulator of cell proliferation, survival, and migration and the enzyme that dephosphorylates it, phosphatase and tensin homolog (PTEN), is an important tumor suppressor. As excess PIP3 signaling is a hallmark of many cancers, its suppression through activation of PTEN is a potential cancer intervention. Using a heterologous expression system in which human PTEN-GFP is expressed in Dictyostelium cells, we identified mutations in the membrane-binding regulatory interface that increase the recruitment of PTEN to the plasma membrane due to enhanced association with PI(4,5)P2. We engineered these into an enhanced PTEN (ePTEN) with approximately eightfold increased ability to suppress PIP3 signaling. Upon expression in human cells, ePTEN decreases PIP3 levels in the plasma membrane; phosphorylation of AKT, a major downstream event in PIP3 signaling; and cell proliferation and migration. Thus, the activation of PTEN can readjust PIP3 signaling and may serve as a feasible target for anticancer therapies.

| S-EPMC4084459 | biostudies-literature

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