The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling

Mirjam T Epping; Liming Wang; Michael J Edel; Leone Carlée; Maria Hernandez; René Bernards

doi:10.1016/j.cell.2005.07.003

The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling

Cell. 2005 Sep 23;122(6):835-47. doi: 10.1016/j.cell.2005.07.003.

Authors

Mirjam T Epping¹, Liming Wang, Michael J Edel, Leone Carlée, Maria Hernandez, René Bernards

Affiliation

¹ Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

PMID: 16179254
DOI: 10.1016/j.cell.2005.07.003

Abstract

Retinoic acid (RA) induces proliferation arrest, differentiation, and apoptosis, and defects in retinoic acid receptor (RAR) signaling have been implicated in cancer. The human tumor antigen PRAME is overexpressed in a variety of cancers, but its function has remained unclear. We identify here PRAME as a dominant repressor of RAR signaling. PRAME binds to RAR in the presence of RA, preventing ligand-induced receptor activation and target gene transcription through recruitment of Polycomb proteins. PRAME is present at RAR target promoters and inhibits RA-induced differentiation, growth arrest, and apoptosis. Conversely, knockdown of PRAME expression by RNA interference in RA-resistant human melanoma restores RAR signaling and reinstates sensitivity to the antiproliferative effects of RA in vitro and in vivo. Our data suggest that overexpression of PRAME frequently observed in human cancers confers growth or survival advantages by antagonizing RAR signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism*
Antigens, Neoplasm / pharmacology
Apoptosis / drug effects
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
DNA-Binding Proteins / metabolism
Enhancer of Zeste Homolog 2 Protein
Humans
Ligands
Melanoma / drug therapy
Melanoma / metabolism*
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Polycomb Repressive Complex 2
Protein Binding
RNA Interference / physiology
Receptors, Retinoic Acid / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Repressor Proteins / pharmacology
Sensitivity and Specificity
Signal Transduction / drug effects
Signal Transduction / physiology*
Transcription Factors / metabolism
Transplantation, Heterologous
Tretinoin / antagonists & inhibitors
Tretinoin / metabolism

Substances

Antigens, Neoplasm
DNA-Binding Proteins
Ligands
PRAME protein, human
Receptors, Retinoic Acid
Repressor Proteins
Transcription Factors
Tretinoin
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2