Identification of a methylation hotspot in the death receptor Fas/CD95 in bladder cancer

Watson, Chris; O'Kane, Hugh F.; Maxwell, Perry; Sharaf, Osama; Peták, István; Hyland, Paula L.; O'Rouke, D.; McKnight, John; Canning, Paul; Williamson, Kate E.

doi:10.3892/ijo.2011.1250

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…Reduced expression of FAS has been recurrently reported in the literature as an important mechanism, whereby tumor cells may resist towards FAS-mediated apoptotic signaling. Evidence for FAS downregulation has been shown in bladder cancer, 29 primary cutaneous T-cell lymphoma, 30 myeloid leukemia cells, 31 melanoma, 32 colorectal carcinoma 33 or breast cancer. 34 Moreover, FAS expression levels have been determined in two independent array-based expression profiling studies comparing T-ALL and T-LBL human samples (GEO accession numbers GSE1577 and GSE29986).…”

Section: Discussionmentioning

confidence: 99%

FAS system deregulation in T-cell lymphoblastic lymphoma

et al. 2014

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The acquisition of resistance towards FAS-mediated apoptosis may be required for tumor formation. Tumors from various histological origins exhibit FAS mutations, the most frequent being hematological malignancies. However, data regarding FAS mutations or FAS signaling alterations are still lacking in precursor T-cell lymphoblastic lymphomas (T-LBLs). The available data on acute lymphoblastic leukemia, of precursor origin as well, indicate a low frequency of FAS mutations but often report a serious reduction in FAS-mediated apoptosis as well as chemoresistance, thus suggesting the occurrence of mechanisms able to deregulate the FAS signaling pathway, different from FAS mutation. Our aim at this study was to determine whether FAS-mediated apoptotic signaling is compromised in human T-LBL samples and the mechanisms involved. This study on 26 T-LBL samples confirms that the FAS system is impaired to a wide extent in these tumors, with 57.7% of the cases presenting any alteration of the pathway. A variety of mechanisms seems to be involved in such alteration, in order of frequency the downregulation of FAS, the deregulation of other members of the pathway and the occurrence of mutations at FAS. Considering these results together, it seems plausible to think of a cumulative effect of several alterations in each T-LBL, which in turn may result in FAS/FASLG system deregulation. Since defective FAS signaling may render the T-LBL tumor cells resistant to apoptotic cell death, the correct prognosis, diagnosis and thus the success of anticancer therapy may require such an in-depth knowledge of the complete scenario of FAS-signaling alterations.

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Section: Discussionmentioning

confidence: 99%

FAS system deregulation in T-cell lymphoblastic lymphoma

et al. 2014

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“…Besides induction of broad gene expression changes affecting various cellular processes, epigenetic inhibitors (epidrugs) can also remodel the differentiation and the immune phenotypes of both cancer and immune cells ( 6 , 7 ). Epidrugs can also influence key components of apoptosis signaling in cells, e.g., expression of the FAS receptor (CD95) is regulated by DNA methylation ( 8 ). Concurringly, epidrugs have been shown to resensitize tumors to previously failed therapies and to affect both the cancer cells as well as the tumor microenvironment ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells

et al. 2021

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BackgroundTreatment of B-cell malignancies with CD19-directed chimeric antigen receptor (CAR) T-cells marked a new era in immunotherapy, which yet has to be successfully adopted to solid cancers. Epigenetic inhibitors of DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) can induce broad changes in gene expression of malignant cells, thus making these inhibitors interesting combination partners for immunotherapeutic approaches.MethodsUrothelial carcinoma cell lines (UCC) and benign uroepithelial HBLAK cells pretreated with the DNMTi decitabine or the HDACi romidepsin were co-incubated with CAR T-cells directed against EGFR or CD44v6, and subsequent cytotoxicity assays were performed. Effects on T-cell cytotoxicity and surface antigen expression on UCC were determined by flow cytometry. We also performed next-generation mRNA sequencing of inhibitor-treated UCC and siRNA-mediated knockdown of potential regulators of CAR T-cell killing.ResultsExposure to decitabine but not romidepsin enhanced CAR T-cell cytotoxicity towards all UCC lines, but not towards the benign HBLAK cells. Increased killing could neither be attributed to enhanced target antigen expression (EGFR and CD44v6) nor fully explained by changes in the T-cell ligands PD-L1, PD-L2, ICAM-1, or CD95. Instead, gene expression analysis suggested that regulators of cell survival and apoptosis were differentially induced by the treatment. Decitabine altered the balance between survival and apoptosis factors towards an apoptosis-sensitive state associated with increased CAR T-cell killing, while romidepsin, at least partially, tilted this balance in the opposite direction. Knockdown experiments with siRNA in UCC confirmed BID and BCL2L1/BCLX as two key factors for the altered susceptibility of the UCC.ConclusionOur data suggest that the combination of decitabine with CAR T-cell therapy is an attractive novel therapeutic approach to enhance tumor-specific killing of bladder cancer. Since BID and BCL2L1 are essential determinants for the susceptibility of a wide variety of malignant cells, their targeting might be additionally suitable for combination with immunotherapies, e.g., CAR T-cells or checkpoint inhibitors in other malignancies.

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“…The death-inducing signaling complex (DISC), which contains oligomerized Fas, the adaptor protein Fas-associated death domain (FADD), two isoforms of procaspase-8, procaspase-10 and cellular FADD-like interleukin (IL)-1β-converting enzyme-inhibitory protein, is formed following FasL stimulation (4), resulting in the induction of programmed cell death or apoptosis (5). Downregulated expression of Fas has been observed in numerous types of tumor, including head and neck, esophageal, pancreatic, non-small cell lung and bladder cancer (4–8). …”

Section: Introductionmentioning

confidence: 99%

Fas expression is downregulated in gastric cancer

Wang

Chen

et al. 2016

Molecular Medicine Reports

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The aim of the present study was to investigate Fas expression in tumor samples from patients with gastric cancer, in order to determine the involvement of the Fas signaling pathway. The protein expression levels of Fas, caspase-8, caspase-3 and poly (adenosine diphosphate-ribose) polymerase 1 (PARP1) were examined in gastric cancer specimens and their associations with clinical pathological parameters were analyzed with immunohistochemical staining and western blot analysis. The mRNA expression was quantified with quantitative PCR and apoptosis was examined with a FACScan flow cytometer. The results demonstrated that the downregulation of Fas expression was correlated with less histological differentiation, gender (male), and increased lymph node and distant metastases (P<0.05). In the AGS established gastric cancer cell line, upregulation of the Fas signaling pathway promoted the apoptosis of gastric cancer cells by upregulating the expression of caspase-8 and caspase-3, and downregulating the expression of PARP1. The present study demonstrated that Fas was associated with gastric cancer and promoted the apoptosis of gastric cancer cells via caspase-8, caspase-3 and PARP1. These results suggested that caspase-8, caspase-3 and PARP1 may be triggers of gastric cancer, and upregulation of caspase-8 and caspase-3 expression, or inhibition of PARP1 expression may improve the therapeutic outcome in patients with gastric cancer.

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Identification of a methylation hotspot in the death receptor Fas/CD95 in bladder cancer

Cited by 8 publications

References 36 publications

FAS system deregulation in T-cell lymphoblastic lymphoma

FAS system deregulation in T-cell lymphoblastic lymphoma

Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells

Fas expression is downregulated in gastric cancer

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