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SNF5, a core subunit of SWI/SNF complex, regulates melanoma cancer cell growth, metastasis, and immune escape in response to matrix stiffness.

ABSTRACT: Increased stiffness of the extracellular matrix is an important hallmark of melanoma development and progression, but its regulatory role and related mechanisms remain unclear. We adapted polydimethylsiloxane (PDMS)-micropillar-based matrix platform and investigated the effect of matrix stiffness on the proliferation, epithelial-mesenchymal transition (EMT), and immune escape of melanoma cells. We observed a stiff matrix enhanced cell proliferation, EMT, and immune escape of A375 cells. Furthermore, the expression of SNF5 on the stiffer matrix was higher than that on the softer matrix. Next, we investigated whether SNF5 is an important transducer in response to matrix stiffness. Our results revealed that knockdown of SNF5 significantly decreased stiff matrix-induced activation of cell proliferation, EMT and immune escape. Meanwhile, the overexpression of SNF5 showed its ability to increase cell proliferation, invasion and immune escape by activating the STAT-3 pathway in vitro. Furthermore, SNF5 deficiency elevated the level of tumor-infiltrating CD8⁺T cells and decreased the number of PD-L1 positive cells in vivo. Together, our findings suggested that stiffer substrate enhanced melanoma development by upregulating SNF5 expression, and SNF5 is a key mediator of stiffer matrix-induced immune evasion of melanoma cancer cells.

SUBMITTER: Chen Y

PROVIDER: S-EPMC8749166 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation.

Project description:Regulation of gene expression underlies cell differentiation and organogenesis. Both transcription factors and chromatin modifiers are crucial for this process. To study the role of the ATP-dependent SWI/SNF chromatin-remodeling complex in cell differentiation, we inactivated the gene encoding the core complex subunit SNF5/INI1 in the developing liver. Hepatic SNF5 deletion caused neonatal death due to severe hypoglycemia; mutant animals fail to store glycogen and have impaired energetic metabolism. The formation of a hepatic epithelium is also affected in SNF5-deficient livers. Transcriptome analyses showed that SNF5 inactivation is accompanied by defective transcriptional activation of 70% of the genes that are normally upregulated during liver development. These include genes involved in glycogen synthesis, gluconeogenesis and cell-cell adhesion. A fraction of hepatic developmentally activated genes were normally expressed, suggesting that cell differentiation was not completely blocked. Moreover, SNF5-deleted cells showed increased proliferation and we identified several misexpressed genes that may contribute to cell cycle deregulation in these cells. Our results emphasize the role of chromatin remodeling in the activation of cell-type-specific genetic programs and driving cell differentiation.

| S-EPMC1224692 | biostudies-literature

Evaluation of the role of downregulation of SNF5/INI1 core subunit of SWI/SNF complex in clear cell renal cell carcinoma development.

Project description:Clear cell renal cell carcinoma (ccRCC) is characterized by stabilization of hypoxia-inducible factor (HIF1), and mutations in von Hippel-Lindau (VHL) gene. Additionally, in about 40% of ccRCC cases the mutation in PBRM1 (POLYBROMO1) gene coding for a non-core subunit of SWI/SNF chromatin remodeling complex was found suggesting potential impairment of this complex function in ccRCC. In this study we assessed the extent to which the core SWI/SNF complex subunit - INI1 (hSNF5/SMARCB1) is affected in ccRCC and whether it has any consequences on the development of this type of cancer. The evaluation of INI1 protein level in samples from 50 patients with diagnosed ccRCC, including three displaying rhabdoid features, showed the INI1 positive staining in rhabdoid cells while the conventional ccRCC cells exhibited reduced INI1 level. This indicated the rhabdoid component of ccRCC as distinct from other known rhabdoid tumors. The reduced INI1 protein level observed in all conventional ccRCC cases used in this study correlated with decreased SMARCB1 gene expression at the transcript level. Consistently, the overexpression of INI1 protein in A498 ccRCC cell line resulted in the elevation of endogenous SMARCB1 transcript level indicating that the INI1-dependent regulatory feedback loop controlling expression of this gene is affected in ccRCC Moreover, the set of INI1 target genes including i.e. CXCL12/CXCR7/CXCR4 chemokine axis was identified to be affected in ccRCC. In summary, we demonstrated that the inactivation of INI1 may be of high importance for ccRCC development and aggressiveness.

| S-EPMC5714755 | biostudies-literature

Loss of Snf5 Induces Formation of an Aberrant SWI/SNF Complex.

Project description:The SWI/SNF chromatin remodeling complex is highly conserved from yeast to human, and aberrant SWI/SNF complexes contribute to human disease. The Snf5/SMARCB1/INI1 subunit of SWI/SNF is a tumor suppressor frequently lost in pediatric rhabdoid cancers. We examined the effects of Snf5 loss on the composition, nucleosome binding, recruitment, and remodeling activities of yeast SWI/SNF. The Snf5 subunit is shown by crosslinking-mass spectrometry (CX-MS) and subunit deletion analysis to interact with the ATPase domain of Snf2 and to form a submodule consisting of Snf5, Swp82, and Taf14. Snf5 promotes binding of the Snf2 ATPase domain to nucleosomal DNA and enhances the catalytic and nucleosome remodeling activities of SWI/SNF. Snf5 is also required for SWI/SNF recruitment by acidic transcription factors. RNA-seq analysis suggests that both the recruitment and remodeling functions of Snf5 are required in vivo for SWI/SNF regulation of gene expression. Thus, loss of SNF5 alters the structure and function of SWI/SNF.

| S-EPMC5424545 | biostudies-literature

The core SWI/SNF catalytic subunit Brg1 regulates nephron progenitor cell proliferation and differentiation.

Project description:Chromatin-remodeling complexes play critical roles in establishing gene expression patterns in response to developmental signals. How these epigenetic regulators determine the fate of progenitor cells during development of specific organs is not well understood. We found that genetic deletion of Brg1 (Smarca4), the core enzymatic protein in SWI/SNF, in nephron progenitor cells leads to severe renal hypoplasia. Nephron progenitor cells were depleted in Six2-Cre, Brg1flx/flx mice due to reduced cell proliferation. This defect in self-renewal, together with impaired differentiation resulted in a profound nephron deficit in Brg1 mutant kidneys. Sall1, a transcription factor that is required for expansion and maintenance of nephron progenitors, associates with SWI/SNF. Brg1 and Sall1 bind promoters of many progenitor cell genes and regulate expression of key targets that promote their proliferation.

| S-EPMC7520014 | biostudies-literature

The chromatin remodeling and mRNA splicing functions of the Brahma (SWI/SNF) complex are mediated by the SNR1/SNF5 regulatory subunit.

Project description:Nucleosome remodeling catalyzed by the ATP-dependent SWI/SNF complex is essential for regulated gene expression. Transcriptome profiling studies in flies and mammals identified cell cycle and hormone responsive genes as important targets of remodeling complex activities. Loss of chromatin remodeling function has been linked to developmental abnormalities and aggressive cancers. The Drosophila Brahma (Brm) SWI/SNF complex assists in reprogramming and coordinating gene expression in response to ecdysone hormone signaling at critical points during development. We used RNAi knockdown in cultured cells and transgenic flies, and conditional mutant alleles to identify unique and important functions of two conserved Brm complex core subunits, SNR1/SNF5 and BRM/SNF2-SWI2, on target gene regulation. Unexpectedly, we found that incorporation of a loss of function SNR1 subunit led to alterations in RNA polymerase elongation, pre-mRNA splicing regulation and chromatin accessibility of ecdysone hormone regulated genes, revealing that SNR1 functions to restrict BRM-dependent nucleosome remodeling activities downstream of the promoter region. Our results reveal critically important roles of the SNR1/SNF5 subunit and the Brm chromatin remodeling complex in transcription regulation during elongation by RNA Polymerase II and completion of pre-mRNA transcripts that are dependent on hormone signaling in late development.

| S-EPMC3401471 | biostudies-literature

Yeast SWI/SNF complex - Loss of Snf5 Induces Formation of an Aberrant SWI/SNF Complex

Project description:This project uses crosslinked based mass spectrometry (CXMS) to study the architecture of yeast SWI/SNF complex.

2018-06-14 | PXD005948 | Pride

SWI/SNF complex, promising target in melanoma therapy: Snapshot view.

Project description:Therapeutic strategies based on epigenetic regulators are rapidly increasing in light of recent advances in discovering the role of epigenetic factors in response and sensitivity to therapy. Although loss-of-function mutations in genes encoding the SWItch/Sucrose NonFermentable (SWI/SNF) subunits play an important role in the occurrence of ~34% of melanomas, the potential of using inhibitors and synthetic lethality interactions between key subunits of the complex that play an important role in melanoma progression must be considered. Here, we discuss the importance of the clinical application of SWI/SNF subunits as a promising potential therapeutic in melanoma.

| S-EPMC9947295 | biostudies-literature

The SWI/SNF subunit Bcl7a contributes to motor coordination and Purkinje cell function.

Project description:Chromatin remodelers have emerged as prominent regulators of epigenetic processes and potential drivers of various human pathologies. The multi-subunit chromatin-remodeling SWI/SNF complex determines gene expression programs and, consequently, contributes to the differentiation, maturation and plasticity of neurons. Here, we investigate the elusive biological function of Bcl7a and Bcl7b, two newly identified subunits of the SWI/SNF complex that are highly expressed throughout the brain. We generated ubiquitous and neuron-specific Bcl7a and Bcl7b single and double knockout mice. We provide evidence that Bcl7b is dispensable for animal survival as well as behavioral plasticity. Conversely, ubiquitous Bcl7a knockout results in perinatal lethality, while genetic deletion of Bcl7a in postmitotic neurons elicits motor abnormalities and affects dendritic branching of Purkinje cells, with no obvious synergistic relationship with Bcl7b. Collectively, our findings reveal novel insights into the cellular processes linked to BCL7-containing SWI/SNF complexes and their unrecognized roles in the brain.

| S-EPMC5719005 | biostudies-literature

The core SWI/SNF catalytic subunit Brg1 regulates nephron progenitor cell proliferation and differentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-02-19 | GSE196997 | GEO

Extracellular matrix-regulated gene expression requires cooperation of SWI/SNF and transcription factors.

Project description:Extracellular cues play crucial roles in the transcriptional regulation of tissue-specific genes, but whether and how these signals lead to chromatin remodeling is not understood and subject to debate. Using chromatin immunoprecipitation assays and mammary-specific genes as models, we show here that extracellular matrix molecules and prolactin cooperate to induce histone acetylation and binding of transcription factors and the SWI/SNF complex to the beta- and gamma-casein promoters. Introduction of a dominant negative Brg1, an ATPase subunit of SWI/SNF complex, significantly reduced both beta- and gamma-casein expression, suggesting that SWI/SNF-dependent chromatin remodeling is required for transcription of mammary-specific genes. Chromatin immunoprecipitation analyses demonstrated that the ATPase activity of SWI/SNF is necessary for recruitment of RNA transcriptional machinery, but not for binding of transcription factors or for histone acetylation. Co-immunoprecipitation analyses showed that the SWI/SNF complex is associated with STAT5, CCAAT/enhancer-binding protein beta, and glucocorticoid receptor. Thus, extracellular matrix- and prolactin-regulated transcription of the mammary-specific casein genes requires the concerted action of chromatin remodeling enzymes and transcription factors.

| S-EPMC2933196 | biostudies-literature

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