Regulation of MGAT5 expression by epigenetic mechanisms, its impact on the TIMP-1/CD63/B1-Integrin axis and possible therapeutic strategies

• Grant number: 23/06004-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2024
• End date: March 31, 2028
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Miriam Galvonas Jasiulionis
• Grantee: Beatriz Laís Justo Saraiva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Glycosylation is the main post-translational change that proteins undergo and plays a fundamental role in several physiological processes. Changes in glycosylation patterns are associated with different pathological processes, including cancer. The presence of atypical glycosidic structures on the surface of tumor cells is correlated with the progression, invasion and metastatic capacity of these cells. Among the aberrant patterns considered "trademarks" of tumor cells, the atypical complex quaternary structures formed by the enzymatic activity of ²-1,6-N-Acetylglucosaminyltransferase V (GnT-V) stand out. The contribution of GnT-V to the development, progression and tumor metastasis is well documented since GnT-V targets different proteins involved in processes such as loss of cell-cell and cell-extracellular matrix adhesion, induction of resistance to anoikis, protection, survival, EMT, migration and invasion of tumor cells and also escape from the immune system. In our laboratory, using cell lines that represent a melanoma progression model, we identified TIMP-1, CD63 and ²1-Integrins - proteins that form a membrane complex responsible for activating different intracellular signaling pathways - as targets of GnT-V. Although GnT-V has increased expression and activity in different tumor cells, contributing to tumor progression and metastasis, little is known about the processes involved in the transcriptional regulation of MGAT5, both in physiological processes and in cancer. Therefore, this project aims to verify whether epigenetic mechanisms regulate the expression of MGAT5, identify what these epigenetic mechanisms are and develop therapeutic strategies based on epigenetic modulation that involve silencing MGAT5. Furthermore, this project also aims to investigate the impact of MGAT5 on the TIMP-1/CD63/²1-Integrin complex and the different functions that TIMP1 exerts in the tumor.