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| Author(s): |
Joice Moraes Menezes
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2024-07-29 |
| Examining board members: |
Cesar Seigi Fuziwara;
Nathalie Cella;
Paula Paccielli Freire;
Cibele Masotti
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| Advisor: | Cesar Seigi Fuziwara |
| Abstract | |
Lung cancer is the main contributor to cancer-related mortality, accounting for over one million annual fatalities worldwide. Lung adenocarcinoma is the most common form of lung cancer and has an average 5-yr survival rate of 15%, mainly due to the asymptomatic progression of the disease and late-stage detection. Overexpression of Polycomb group (PcG) proteins, particularly EZH2, has been associated with the pathogenesis of lung cancer, often directly correlating with advanced metastatic dissemination and poor prognosis. Nonetheless, the consequences of EZH2 dysregulation in lung cancer remain to be elucidated. In this study, EZH2 expression was modulated by CRISPR/Cas9-mediated gene editing and pharmacologically inhibited with the EZH2 inhibitor EPZ6438. The results showed that CRISPR/Cas9-induced EZH2 gene editing reduced cell growth, cell migration, invasion, and reduced colony formation in vitro. Moreover, the luciferase reporter for NF-B signaling showed reduction of activity in EZH2-edited cells, indicating an antitumoral effect together with the functional results. Analysis of the expression of lung differentiation genes showed that EZH2 inhibition caused an increase in the transcription factors GATA5, FOXA2 and lung surfactants, indicating a pro-differentiation effect. However, EZH2-edited cells injected into an immunocompromised mouse model exhibited a substantial increase in tumor growth as well as an increase in other PcG genes, suggesting a cooperative and compensatory effect between the complexes. These results could be of high clinical relevance both elucidating the mechanisms of new molecular targets and informing the treatment approach for lung cancer with epigenetic therapies. (AU) | |
| FAPESP's process: | 22/03730-9 - Effect of the modulation of EZH2/PRC in lung cancer |
| Grantee: | Joice Moraes Menezes |
| Support Opportunities: | Scholarships in Brazil - Master |