Effect of Emerin knockdown on cellular response to cisplatin-induced DNA damage in glioblastoma cell lines with different p53 status

• Grant number: 23/10816-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2023
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Fábio Luis Forti
• Grantee: Donna Joe Farfan Hilares
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Changes in the nucleus of cancer cells are frequent and widely used in the diagnosis and prognosis of cancer patients, since that have been related to tumor aggressiveness, invasion and metastasis. Emerin is a nuclear membrane protein that plays an important role in the integrity of the nuclear architecture ando also important for gene expression, cell signaling, and chromatin organization and stability. Due to its direct interaction with components of the LINC complex, which connects the cytoskeleton and the nucleoskeleton, Emerin participates in the communication between these two compartments. Furthermore, it interacts with nuclear actin and may be involved in the regulation of F-actin in the cytoplasm and nucleus. The LINC complex and nuclear actin have been shown to participate in the maintenance of stability and integrity of genome, while recent studies described the participation of Emerin in the migration, invasion and metastasis of tumor cells. In invasive breast cancer cell lines, for example, a direct role for Emerin in migration and metastasis has been proposed, depending on its interaction with laminae, nuclear actin and the LINC complex. These considerations are quite lacking in human glioblastomas, especially under conditions of genotoxic stress. These cells have a particularly complicated nature given their high aggressiveness, invasiveness, progression and resistance to therapies. Our research group has recently shown the direct involvement of the actin cytoskeleton in the control of DNA repair in glioblastomas upon different types of genotoxic stress that mimic therapies used in clinical medicine. Therefore, this project aims to evaluate the effect of Emerin knockdown in GBM strains with different p53 status and exposed to treatment with the genotoxic agent cisplatin. This investigation can contribute to the better understanding of molecular mechanisms responsible for the sensitivity/resistance of glioblastomas to therapies and in the search for new perspectives and therapeutic targets, as well as to broaden the understanding of the functions of Emerin in the modulation of the nuclear actin cytoskeleton.