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SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE213260 | GEO | 2023/07/12

REPOSITORIES: GEO

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SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-β-independent manner.

Project description:Histone-lysine N-methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial-to-mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor-beta-independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA-seq and assay for transposase-accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild-type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell-intrinsic and cell-extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis.

| S-EPMC10766198 | biostudies-literature

SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [RNA-Seq]

Project description:SETD2 is one of most frequently mutated genes in renal cell carcinoma. It is generally known as the only histone methyltransferase that catalyze the trimethylation of lysine 36 on histone H3 (H3K36me3). Mutation of this gene and/or loss of its mark have been linked to metastasis and worse patient outcomes in kidney cancer. In this paper, we will examine the mechanism by which SETD2 loss induces epithelial-to-mesenchymal transition (EMT), which is a major pathway that drives invasion and early metastasis in various cancer types. To achieve the goals, we performed several omics analysis including RNA-seq, ChIP-seq and ATAC-seq to characterize how SETD2 deletion alters transcriptome and epigenome.

2023-07-12 | GSE213258 | GEO

SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [ChIP-Seq]

2023-07-12 | GSE213257 | GEO

SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [ATAC-Seq]

2023-07-12 | GSE213256 | GEO

SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner

Project description:SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner

| PRJNA880278 | ENA

SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [ATAC-Seq]

Project description:SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [ATAC-Seq]

| PRJNA880282 | ENA

SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [RNA-Seq]

Project description:SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [RNA-Seq]

| PRJNA880283 | ENA

SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [ChIP-Seq]

Project description:SETD2 loss in renal epithelial cells drives epithelial to mesenchymal transition in a TGFβ-independent manner [ChIP-Seq]

| PRJNA880284 | ENA

TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

| S-EPMC8699757 | biostudies-literature

The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial-mesenchymal transition in a sumoylation-regulated manner.

Project description:Epithelial-mesenchymal transition (EMT) is a fundamental cellular process in epithelial tissue development, and can be reactivated in cancer contributing to tumor invasiveness and metastasis. The cytokine transforming growth factor-β (TGFβ) is a key inducer of EMT, but the mechanisms that regulate TGFβ-induced EMT remain incompletely understood. Here, we report that knockdown of the ubiquitin ligase Smurf2 promotes the ability of TGFβ to induce EMT in a three-dimensional cell culture model of NMuMG mammary epithelial cells. In other studies, we identify Smurf2 as a target of the small ubiquitin like modifier (SUMO) pathway. We find that the SUMO-E2 conjugating enzyme Ubc9 and the SUMO E3 ligase PIAS3 associate with Smurf2 and promote its sumoylation at the distinct sites of Lysines 26 and 369. The sumoylation of Smurf2 enhances its ability to induce the degradation of the TGFβ receptor and thereby suppresses EMT in NMuMG cells. Collectively, our data reveal that Smurf2 acts in a sumoylation-regulated manner to suppress TGFβ-induced EMT. These findings have significant implications for our understanding of epithelial tissue development and cancer.

| S-EPMC4832106 | biostudies-literature

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