PRAME/EZH2-Mediated Regulation of TRAIL: A New Target for Cancer Therapy

D.   D.   De Carvalho; B.   P.   Mello; W.   O.   Pereira; G.   P.   Amarante-Mendes

Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts a cancer cell-specific pro-apoptotic activity. This property made the TRAIL associated pathway one of the most promising strategies aimed at inducing tumor-selective death. In fact, several approaches have been considered to explore this pathway for cancer therapy, such as recombinant TRAIL, agonist antibodies for TRAIL receptors, and adenoviral TRAIL. However, all of these approaches have certain disadvantages that limit their clinical use. Our recent discovery that the complex PRAME/EZH2 is able to repress TRAIL expression, in a cancer-specific manner, suggests an alternative approach for combined cancer therapy. A genetic or pharmacological inhibition of TRAIL repressors in cancer cells could restore endogenous TRAIL expression, thereby overcoming some of the limitations of and/or cooperating with previous approaches.

Keywords: Apoptosis, cancer, EZH2, polycomb genes, PRAME, TRAIL, tumor necrosis factor, chromosome, natural killer cell, inflammation, autoimmune diseases, macrophages, metalloproteases, osteoprotegerin, conformational modification.