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Characterization of ubiquitination and acetylation processes during mesenchymal-epithelial transition in breast cancer models

Grant number: 23/07138-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): January 01, 2024
Effective date (End): January 31, 2025
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Vitor Marcel Faça
Grantee:Izadora Archiolli
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Cancer is a set of multifactorial diseases that generate disorderly growing cells, forming malignant tumors that can invade adjacent tissues or distant organs through the process of metastasis, which is ultimately responsible for lethality of these diseases. One of the molecular mechanisms that occurs during metastasis is the epithelial-mesenchymal transition (EMT). EMT is regulated for multiple factors that enhance the cells capacity to detach from the primary tumor mass, enter the circulation and create secondary sites of disease. Several studies have indicated that post-translational modifications such as acetylation, ubiquitination and deubiquitination are closely associated with EMT, either promoting or inhibiting tumor progression. For instance, the deubiquitinase enzyme USP7 has been described as a player in this process. Additionally, the acetylation and ubiquitination processes are directly correlated, competitors and finely regulated. Understanding the crosstalk between these modifications in tumor progression has become an important research focus. In this project, we aim to employ the strategy of capturing specific ubiquitinated and acetylated proteins using antibodies for immunopurification. This immunoaffinity-based approach will be applied for in vitro cell models of EMT, derived from mammary gland adenocarcinoma. These cell models will be induced to undergo EMT using the growth factor EGF or other stimuli, and concomitantly, the homologous deubiquitinases USP7 and USP47 will be inhibited using P5091, and the histone deacetilase HDAC1 will be inhibited with SAHA. Proteins extracted from these models will be enriched for ubiquitinated and acetylated sites and analyzed quantitatively isobaric labeling with TMT and highthroughput and targeted proteomics. This strategy will enable identification of distinct proteins involved in the EMT process and new targets for these important post-traducionall modifications at different stages of tumor progression. Moreover, this strategy might shed light on the roles of deubiquitinases and acetylases in breast cancer and uncover proteins involved in control of tumor progression that could serve as potential therapeutic targets.

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