<i>In Vivo</i> Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

Santos, Mirentxu; Martínez‐Fernández, Mónica; Dueñas, Marta; García‐Escudero, Ramón; Alfaya, Begoña; Villacampa, Felipe; Sáiz-Ladera, Cristina; Costa, Clotilde; Oteo, Marta; Duarte, José; Martínez, Víctor G.; Gómez-Rodriguez, Ma José; Martı́n, Ma Luisa; Fernández, Manoli; Viatour, Patrick; Morcillo, Miguel Angel; Sage, Julien; Castellano, Daniel; Rodríguez-Peralto, José L.; Rosa, Federico de la; Paramio, Jesús M.

doi:10.1158/0008-5472.can-14-1218

Cited by 79 publications

(100 citation statements)

References 49 publications

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“…We found that tumors showing positive EZH2 staining dictated early recurrence (Figure 2A, 2B) and progression (Figure 2D), in agreement with our previous findings [7]. However, the increased EZH2 gene expression levels (Figure 2C) was not predictive of early recurrence in NMIBC (Figure 2C), reinforcing a possible post-transcriptional modulation of EZH2.…”

Section: Resultssupporting

confidence: 90%

Opposing roles of PIK3CA gene alterations to EZH2 signaling in non-muscle invasive bladder cancer

et al. 2017

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The high rates of tumor recurrence and progression represent a major clinical problem in non-muscle invasive bladder cancer. Previous data showed that EZH2-dependent signaling mediates these processes, whereas the frequent alterations of PIK3CA gene (copy gains and mutations) are predictive of reduced recurrence. Here we show, using clinical samples and bladder cancer cell lines, a functional interaction between EZH2- and PIK3CA-dependent signaling pathways. PIK3CA alterations mediated, on the one hand, the increased expression of two miRNAs, miR-101 and miR-138, which posttranscriptionally downregulate EZH2 expression. On the other hand, PIK3CA alterations facilitate the activation of Akt which phosphorylates EZH2 on Ser21, precluding the trimethylation of histone H3 in K27. Remarkably the increased expression of miR101 or miR138 and the expression of Ser21-phosphorylated EZH2 are good prognostic factors regarding non-muscle invasive bladder cancer recurrence and progression. Collectively, this study provides molecular evidences indicating that the gene expression rewiring occurring in primary bladder tumors, associated with increased EZH2 expression and activity and mediating the increased recurrence and progression risk, are prevented by PIK3CA-dependent signaling. This molecular process may have deep implications in the management of bladder cancer patients and in the design of novel molecularly targeted therapeutic approaches.

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Section: Resultssupporting

confidence: 90%

Opposing roles of PIK3CA gene alterations to EZH2 signaling in non-muscle invasive bladder cancer

et al. 2017

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“…E, Western blot analysis of cyclin D1, cyclin A2, P-Rb and CDK4 in tumour tissues of NC and shE2F4 groups. 49,50 In this study, the Co-IP assay and IF showed that E2F4 directly interacted with EZH2. Bar graphs (mean ± SD) and representative images are shown.…”

Section: F I G U R Ementioning

confidence: 52%

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

Feng

et al. 2020

J Cellular Molecular Medi

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Acute myeloid leukaemia (AML) is an aggressive and mostly incurable haematological malignancy with frequent relapse after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve AML clinical outcome. Here, we aim to study the dysregulation of a particular transcription factor, E2F4, and its role in the progression of AML. In this study, human clinical data from the Gene Expression Profiling Interactive Analysis (GEPIA) revealed that increased E2F4 expression was associated with poor prognosis in AML patients. Moreover, the experimental results showed that E2F4 was aberrantly overexpressed in human AML patients and cell lines. Depletion of E2F4 inhibited the proliferation, induced the differentiation and suppressed the growth of AML cells in a nude mouse model. By contrast, overexpression of E2F4 promoted the proliferation and inhibited the differentiation of AML cells in vitro. Additionally, E2F4 expression not only is positively correlated with EZH2 but also can bind to EZH2. RNA microarray results also showed that E2F4 can regulate MAPK signalling pathway. EZH2 can reverse the inhibitory effect of E2F4 silencing on MAPK signaling pathway. In summary, our data suggest that E2F4 may be a potential therapeutic target for AML therapy.

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“…Indeed the loss of p130 in Rb-deficient cells promotes the development of neuroendocrine lesions in the lungs of mice [10], deletion of Rb and p130 in lung epithelial cells leads to hypercellularity due to defective apoptosis [8]; and p130 acts as a tumor suppressor in the context of Rb and p53 loss (rendering SCLC [9] or NSCLC [30] depending on the targeted cell compartment) or Kras activation (rendering NSCLC [39]). Moreover, using the same mouse model and the same adenoviral vector the development of overt tumors in mouse bladder [15] or liver [40] have been previously reported, and the ablation of retinoblastoma proteins in epidermis using a K14creER promoter to express Cre recombinase also caused spontaneous tumor development in surviving mice [Bornachea O PhD thesis https://repositorio.uam.es/handle/10486/667976]. Overall, these data point to strict differences in tissue susceptibility and that further oncogenic signaling is required to account for malignant tumor development upon ablation of the three retinoblastoma family member genes in mouse lung.…”

Section: Discussionmentioning

confidence: 99%

“…Rb F/F ; p130 F/F ;p107 −/− mice were previously described [15]. Rosa26R reporter animals [23] were purchased to The Jackson Laboratory.…”

Section: Methodsmentioning

confidence: 99%

Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation

et al. 2016

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Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family.

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In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

Cited by 79 publications

References 49 publications

Opposing roles of PIK3CA gene alterations to EZH2 signaling in non-muscle invasive bladder cancer

Opposing roles of PIK3CA gene alterations to EZH2 signaling in non-muscle invasive bladder cancer

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation

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