Abstract B86: Epigenetic regulation of TRAIL mediated by PRAME/EZH2 in cancer.

Abstract

Abstract TRAIL, a member of the TNF ligand family, was shown to selectively kill oncogenically transformed cells and, therefore, to participate in the cell-mediated immunity against tumors. However, TRAIL is down-regulated in a variety of tumor-bearing patients. On the other hand, PRAME (preferentially expressed antigen of melanoma) is frequently overexpressed in a wide variety of malignant diseases. It was shown that PRAME can function as a repressor of retinoic acid receptor and this transcriptional repression depends on the formation of a complex with a member of the polycomb group, EZH2 (enhancer of zeste homolog 2). Interestingly, TRAIL expression can be positively regulated by retinoic acid. Data from our lab revealed that TRAIL is down-regulated and PRAME is up-regulated during the development of chronic myeloid leukemia (CML) and that their normal levels are restored after complete cytogenetic remission (CCR). Furthermore, there was a significant, negative correlation between the expression of PRAME and TRAIL in CML patients. Overexpression of BCR-ABL in the acute promyelocytic leukemia cell line HL-60 increased the levels of PRAME and decreased the levels of TRAIL. Knocking-down of either PRAME or EZH2 in K562 CML cell line resulted in a dramatic up-regulation of TRAIL. We concluded that PRAME up-regulation by BCR-ABL plays an important role in CML pathogenesis by repressing retinoic acid signaling pathway and, consequently, down-regulating TRAIL expression, a potent anti-cancer agent as an inducer of the extrinsic pathway of apoptosis. On the basis of these results, we performed bioinformatics analysis, using the Oncomine Research platform, for PRAME and TRAIL expression on solid tumors. We found several works in which PRAME and TRAIL expressions were negatively correlated. In particular, PRAME was up-regulated while TRAIL was down-regulated in kidney, lung, prostate and sarcoma compared to normal tissues. These expression patterns of PRAME and TRAIL were confirmed by real-time PCR in tumor cell lines of prostate, breast, colon and pharynx. At this moment, we are expanding the validation of bioinformatics data in a larger number of tumor cell lines as well as in tumor and normal tissues from patients with different forms of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B86.