Abstract A28: Targeting PCL3/PHF19 as an alternative therapeutic strategy to EZH2 inhibition in PRC2-deregulated cancers
| العنوان: | Abstract A28: Targeting PCL3/PHF19 as an alternative therapeutic strategy to EZH2 inhibition in PRC2-deregulated cancers |
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| المؤلفون: | Gerard L. Brien, Bracken P. Adrian, Emilia Jerman, Matthew Campbell |
| المصدر: | Cancer Research. 73:A28-A28 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Cancer Research, Tudor domain, biology, EZH2, Cancer, macromolecular substances, Bioinformatics, medicine.disease, Chromatin, Oncology, Cancer research, biology.protein, medicine, Ectopic expression, Epigenetics, PRC1, PRC2 |
| الوصف: | The Polycomb Repressive Complex 2 (PRC2) is emerging as an attractive therapeutic target for the treatment of cancer. Several functional protein domains that are amenable to small-molecule inhibition exist within the complex and the recent development of chemical inhibitors of the EZH1/2 SET domain now offers a means to therapeutically target the complex. Here we explore the potential of targeting the sub-stoichiometric PRC2 component, PCL3/PHF19, as an alternative to EZH1/2 inhibition. We show, both in normal fibroblasts and in SNF5 deficient malignant rhabdoid sarcoma cells, that targeted depletion of PCL3/PHF19 leads to proliferative defects, owing, at least in part, to a loss of Polycomb binding at and de-repression of the tumour suppressor p16INK4A. Significantly, we show that ectopic expression of PCL3/PHF19 leads to p16INK4A repression and a bypass of cellular senescence. This correlates with increased recruitment of EZH2, accumulation of H3K27me3 and PRC1 components on the INK4A promoter, suggesting a potential oncogenic role for PCL3/PHF19. Consistent with this, PCL3/PHF19 is over-expressed in many cancers. Previously we demonstrated that the TUDOR domain of PCL3/PHF19 is required for the ability of the protein to read epigenetic modifications and facilitate the recruitment of EZH2 to chromatin. Taken together with the data presented here, we propose that the TUDOR domain of PCL3/PHF19 represents a viable alternative functional domain within the PRC2 complex for small-molecule inhibition. Citation Format: Gerard L. Brien, Emilia Jerman, Matthew Campbell, Bracken P. Adrian. Targeting PCL3/PHF19 as an alternative therapeutic strategy to EZH2 inhibition in PRC2-deregulated cancers. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A28. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::bb26fc1af1beabe8efb0f8f48b5b2ded https://doi.org/10.1158/1538-7445.cec13-a28 |
| رقم الأكسشن: | edsair.doi...........bb26fc1af1beabe8efb0f8f48b5b2ded |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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