Effects of histone acetyltransferase deregulation in anaplastic thyroid cancer transformation

• Grant number: 23/14065-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: January 29, 2024
• End date: June 28, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Cesar Seigi Fuziwara
• Grantee: Diego Claro de Mello
• Supervisor: Iñigo Landa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Brigham and Women's Hospital (BWH), United States
• Associated to the scholarship: 23/04452-5 - Effect of EZH2/PRC2 modulation in agressive Thyroid Carcinoma, BP.DD

Abstract

Epigenetic deregulation plays a role in progression from the mostly indolent papillary thyroid cancers (PTC) to the anaplastic (ATC) form, which represents one of the most aggressive tumors overall. Mutations in CREBBP and EP300 genes, encoding histone acetyltransferases (HAT), are almost absent in PTC but occur in 15-20% of ATC. HATs are epigenetic regulators that decorate histones with acetyl marks, determining more accessible regions of the genome for subsequent gene expression. In this study, we aim to identify the specific mechanisms by which HAT disruption drives thyroid cancer progression, and to test whether they confer unique therapeutic vulnerabilities that can inform novel treatments for HAT-altered ATCs. To this end, we will employ human- and mouse-derived thyroid cancer specimens with altered HAT function. We will test their roles in the biology of these tumors and will identify specific genomic regions impacted by HAT disruption. We will also employ proteolysis-targeting chimeras (PROTACs) which were specifically synthetized to target HATs and will evaluate whether thyroid cancer cells with mutations in CREBBP/EP300 respond differently to these compounds.