The role of FOXM1 and its cross-talk with MAPK pathway and EZH2 in agressive thyroid cancer

• Grant number: 24/09472-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2024
• End date: August 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Cesar Seigi Fuziwara
• Grantee: Marcella Maringolo Cristovão
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/17282-5 - Transcriptional and post-transcriptional control in aggressive cancer and metastasis, AP.JP

Abstract

Anaplastic thyroid cancer (ATC) is the most aggressive tumor of the endocrine system, displaying a mean survival of 6 months and refractoriness to radioiodine therapy due to the loss of absence of thyroid differentiation and iodine metabolism genes expression. ATC oncogenesis is related to mutation in genes such as TP53, TERT and genes of the MAPK proliferative pathway. Moreover, the overexpression of EZH2, a component of the chromatin remodeling complex PRC2/EZH2, is associated to the silencing of genes involved in cell differentiation, resulting in an undifferentiated phenotype with poor prognosis. In a previous study, we showed that EZH2 promoter region present sites for the transcription factor FOXM1, which when deleted, reduces EZH2 levels. Moreover, preliminary data from this project showed that FOXM1 is overexpressed in ATC compared to less aggressive histotypes of thyroid cancer, and its function is related to the regulation of cell cycle checkpoint proteins and network with different oncogenic pathways. Indeed, our data show that FOXM1 and EZH2 are responsive to MAPK inhibition with U0126, a MEK inhibitor. Thus, the aim of this study is to investigate the role of FOXM1 in anaplastic thyroid cancer, focusing on understanding its interrelationship with EZH2 and MAPK signaling, as modulators of cell processes associated with ATC tumor aggressiveness.