Regulation of TRAIL expression by PRAME and EZH2, as a potential therapeutic target against solid tumors

• Grant number: 12/21680-7
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): March 01, 2013
• Effective date (End): February 28, 2014
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: João Gustavo Pessini Amarante Mendes
• Grantee: Barbara Pereira de Mello
• Supervisor: Scott William Lowe
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Memorial Sloan-Kettering Cancer Center, United States

Abstract

The search for new treatments, more specific and less toxic to fight cancer has been intensified in recent years. Changes in genes that regulate apoptosis, present in most patients with this disease are objects of intense medical research. TRAIL is a protein responsible for triggering the extrinsic pathway of apoptosis, which decrease or loss of its expression is one of the key mechanisms of death evasion by the immune system. Approaches using recombinant TRAIL or agonists of its receptors have been proposed for inducing tumor-specific apoptosis. A recent study conducted in our laboratory, based on one of the processes responsible for conferring advantages on survival or growth of melanoma cells, identified a new mechanism regulating the expression of TRAIL, also involving PRAME and EZH2, suggesting new therapeutic targets to fight Chronic Myelogenous Leukemia (CML). Based on the important results generated in this prior work, and in association with gene expression metanalysis, showing a high expression of PRAME and a low expression of TRAIL in various types of solid tumors compared to their respective normal tissues, we performed an evaluation of the expression of PRAME, EZH2 and TRAIL on human cell lines and tissues, from normal tissues, solid tumors and sarcomas. We observed PRAME overexpressed in tumors, accompanied by decreased expression of TRAIL, in both the results: immunohistochemistry in TMAs (tissue microarrays) and qRT-PCR , as well as a strong negative correlation between TRAIL and EZH2, suggesting that, as seen in CML and hypothesized by us to solid tumors, the presence of a complex consisting of PRAME and EZH2, is responsible for the negative transcriptional regulation of TRAIL in cancer, not only high expression of one of the two genes. Therefore, we propose interfere with the expression of PRAME and/or EZH2, to evaluate if, as suggested by our previous results, these targets might be involved in tumorigenesis, and also to attempt to restore the expression of TRAIL as apoptosis inducer, thus leading the tumor cells to death. (AU)