SWI/SNF chromatin remodeling complex and glucose metabolism are deregulated in advanced bladder cancer

Stachowiak, M.; Szymański, Michał; Ornoch, Anna; Jancewicz, Iga; Rusetska, Natalia; Chrzan, Alicja; Demkow, Tomasz; Siedlecki, Janusz A.; Sarnowski, Tadeusz; Sarnowska, Elżbieta

doi:10.1002/iub.2254

Cited by 12 publications

(13 citation statements)

References 35 publications

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“…Indeed, the mutation rate of SNF5 was only 4% in BC in TCGA dataset (data not shown), which decreased the likelihood of mutation-induced low SNF5 expression in BC. Moreover, Stachowiak et al found a marked decrease in SNF5 protein levels in BC specimens [ 32 ], but a higher SNF5 mRNA level in BC, which suggested that post-transcriptional mechanisms may be involved in the attenuation of SNF5 expression in BC.…”

Section: Discussionmentioning

confidence: 99%

Attenuated expression of SNF5 facilitates progression of bladder cancer via STAT3 activation

et al. 2021

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Background SWI/SNF, a well-known ATP-dependent chromatin-remodeling complex, plays an essential role in several biological processes. SNF5, the core subunit of the SWI/SNF remodeling complex, inactivated in 95% of malignant rhabdoid tumors (MRT), highlighting its significance in tumorigenesis. However, the role of SNF5 in bladder cancer (BC) remains unknown. In this study, we aimed to investigate the function and potential clinical applicability of SNF5 in BC. Methods Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were used to evaluate the clinical significance of SNF5 in BC. We performed Gene Set Enrichment Analysis (GSEA) and functional assays to investigate the role of SNF5 in BC. Genomics of Drug Sensitivity in Cancer (GDSC) and drug-susceptibility tests were performed to identify the potential value of SNF5 in the treatment of BC. Results Low SNF5 expression conferred a poor prognosis and was significantly associated with the N-stage in BC. ROC curves indicated that SNF5 could distinguish BC from the normal tissues. In vitro and in vivo functional assays demonstrated that attenuated SNF5 expression could promote cell proliferation and enhance migration by STAT3 activation. We imputed that low SNF5 expression could confer greater resistance against conventional first-line drugs, including cisplatin and gemcitabine in BC. GDSC and drug-resistance assays suggested that low SNF5 expression renders T24 and 5637 cells high sensitivity to EGFR inhibitor gefitinib, and combination of EZH2 inhibitor GSK126 and cisplatin. Conclusions To the best of our knowledge, the present study, for the first time, showed that low SNF5 expression could promote cell proliferation and migration by activating STAT3 and confer poor prognosis in BC. Importantly, SNF5 expression may be a promising candidate for identifying BC patients who could benefit from EGFR-targeted chemotherapy or cisplatin in combination with EZH2 inhibitor treatment regimens.

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Section: Discussionmentioning

confidence: 99%

Attenuated expression of SNF5 facilitates progression of bladder cancer via STAT3 activation

et al. 2021

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“…As one of the core subunits, SMARCC1 belongs to the SWI/SNF complex, which functions as a key epigenetic complex on genome transcription and consists of 12-14 subunits, including adenosine triphosphatase (ATPase), core, and other accessory subunits (Reisman et al, 2009;Shain and Pollack, 2013;Hohmann and Vakoc, 2014;Alver et al, 2017;Lu and Allis, 2017;Savas and Skardasi, 2018;Lei et al, 2019). A high frequency of mutations with function loss in coding genes of the SWI/SNF complex has been identified by whole genome sequencing in various cancers, especially renal carcinoma and melanoma, implying its important role in tumor suppression (Shain and Pollack, 2013;Stachowiak et al, 2020;Tsuda et al, 2021;Wang et al, 2021;Zhou et al, 2021). Mechanistically, the loss of function of the SWI/SNF complex promotes the transcription of genes related to proliferation and dedifferentiation, impairs DNA repairs, and reduces the antagonistic effect on the PRC complex (Nagl et al, 2005;Wilson et al, 2010;Tolstorukov et al, 2013;Alver et al, 2017;Stanton et al, 2017;Aras et al, 2019;Ribeiro-Silva et al, 2019;Hu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

SMARCC1 Suppresses Tumor Progression by Inhibiting the PI3K/AKT Signaling Pathway in Prostate Cancer

Xiao

Wang

et al. 2021

Front. Cell Dev. Biol.

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BackgroundSWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1) protein is a potential tumor suppressor in various cancers. However, its role in prostate cancer (PCa) remains controversial. The aim of this study was to determine the biological function of SMARCC1 in PCa and explore the underlying regulatory mechanisms.MethodsThe expression of SMARCC1 was validated in PCa tissues by immunohistochemistry. Meanwhile, function experiments were used to evaluate the regulatory role on cell proliferation and metastasis in PCa cells with SMARCC1 depletion both in vitro and in vivo. The expression levels of relevant proteins were detected by Western blotting.ResultsOur finding showed that SMARCC1 was significantly downregulated in prostate adenocarcinoma, with a higher Gleason score (GS) than that in low GS. The decreased expression of SMARCC1 was significantly correlated with a higher GS and poor prognosis. Additionally, we found that silencing of SMARCC1 dramatically accelerated cell proliferation by promoting cell cycle progression and enhancing cell migration by inducing epithelial mesenchymal transition (EMT). Furthermore, depletion of SMARCC1 facilitated PCa xenograft growth and lung metastasis in murine models. Mechanistically, the loss of SMARCC1 activated the PI3K/AKT pathway in PCa cells.ConclusionSMARCC1 suppresses PCa cell proliferation and metastasis via the PI3K/AKT signaling pathway and is a novel therapeutic target.

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“…Among the 18 genes, FBP1 has been reported to serve as a potential biomarker for molecular subtypes of bladder cancer for its participation in glycolysis flux and gluconeogenesis [31]; MGST2 could be induced in bladder cancer cells by Bacillus Calmette-Guérin (BCG) internalization and thus it might act as a novel biomarker of the response to BCG immunotherapy for bladder cancer [32]; TXNIP negatively regulates bladder carcinogenesis by attenuating SDF-1-CXCR4-induced ERK activation [33]; ELF3 can protects bladder cancer cells from epithelial-mesenchymal transition [34]. These above are highly in accordance to our results, supporting the validity of our study strategy.…”

Section: Discussionmentioning

confidence: 99%

A signature of glucose metabolism and DNA methylation improves prognostic prediction for urinary bladder cancer

Liu

Sun

Zhang

et al. 2020

Preprint

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Background: Glucose metabolism and DNA methylation have been previously proved to play important roles in cancers. However, few studies have explored the potential connections between abnormal glucose metabolism and DNA methylation in tumor progression. In this study, we aimed to screen out glucose metabolism-related genes that were DNA methylation associated in order to establish a promising signature for the prognosis of bladder cancer (BLCA).Methods: With transcriptome data of BLCA samples from The Cancer Genome Atlas (TCGA) and methylation data downloaded from TCGA data base 450K microarray, glucose metabolism-related genes that were simultaneously methylation modulated and survival associated were obtained and a prognostic signature was established. Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) were performed for identification of gene and pathway enrichment. Two most methylation-related risky genes were selected to conduct functional validations. Results: 18 target genes were identified and the samples were survival-significantly divided into two groups by using the signature. Via multivariate Cox analysis, we considered the signature an independent prognostic factor. Several biological processes and signaling pathways were enriched in the high-risk group according to GSEA results and three modules of genes were identified by WGCNA. We demonstrated that UCHL1 and PYCR1 promoted proliferation, migration and invasion ability of bladder cancer cells. Conclusions: The signature based on the 18 target genes could serve as an independent prognostic factor for urinary bladder cancer patients.

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SWI/SNF chromatin remodeling complex and glucose metabolism are deregulated in advanced bladder cancer

Cited by 12 publications

References 35 publications

Attenuated expression of SNF5 facilitates progression of bladder cancer via STAT3 activation

Attenuated expression of SNF5 facilitates progression of bladder cancer via STAT3 activation

SMARCC1 Suppresses Tumor Progression by Inhibiting the PI3K/AKT Signaling Pathway in Prostate Cancer

A signature of glucose metabolism and DNA methylation improves prognostic prediction for urinary bladder cancer

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