The Human Tumor Antigen PRAME Is a Dominant Repressor of Retinoic Acid Receptor Signaling

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.

BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

“…We confirmed that PRAME is a target for BCR-ABL tyrosine-kinase signaling pathways and showed that PRAME expression correlates well with BCR-ABL in CML patients, in particular, as a marker of disease progression. Furthermore, our results substantiate the suggestion that PRAME over-expression is involved in tumorigenesis, possibly by suppressing the RA signaling pathway (Epping et al, 2005). PRAME can bind to the RA receptor in the presence of RA and prevent receptor activation and target gene transcription.…”

“…Altogether, these data confirm that PRAME, but not EZH2, is positively regulated by BCR-ABL and that PRAME expression correlates with the progression of CML in our cohort of patients. PRAME is responsible for BCR-ABL-mediated repression of TRAIL In light that PRAME acts as a dominant repressor of RA/RA receptor signaling (Epping et al, 2005) and that TRAIL can be induced by RA treatment (Altucci et al, 2001;Clarke et al, 2004), we established a relationship analysis between the absolute gene expression of PRAME and TRAIL in our cohort of CML patients. We found out a moderate but significant inverse correlation (P ¼ 0.0009, rs ¼ À0.4971) between the expression of these two genes ( Figure 2a).…”

“…EZH2 is required for PRAME-mediated repression of TRAIL Despite the fact that the expression of EZH2 is not modulated by BCR-ABL, EZH2 was shown to be required for the transcriptional repression activity of PRAME (Epping et al, 2005). Therefore, we tested the functional relevance of EZH2 in PRAME-mediated repression of TRAIL.…”

“…Importantly, we found that decreased levels of TRAIL were associated with the progression of the disease. As it is known that TRAIL can respond to retinoic acid (RA) (Walczak et al, 1999;Altucci et al, 2001;Clarke et al, 2004) and that PRAME can act as a dominant repressor of RA/RA receptor signaling (Epping et al, 2005), we decided to investigate a possible association between upregulation of PRAME and decreased levels of TRAIL in CML.…”

Non‐clinical safety evaluation of repeated intramuscular administration of the AS15 immunostimulant combined with various antigens in rabbits and cynomolgus monkeys

“…The PReferentially expressed Antigen of MElanoma (PRAME) was isolated from several types of cancer and may be directly involved in oncogenesis (Epping and Bernards, 2006; Epping et al ., 2005). The recombinant PRAME antigen combined with AS15 (recPRAME + AS15) is currently in clinical development for the treatment of NSCLC (NCT01159964; phase I) and melanoma (NCT01149343; phase I/II).…”