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The transcription factor NFAT plays key roles in multiple biological activities, such as immune responses, tissue development and malignant transformation. NFAT is dephosphorylated by calcineurin, which is activated by intracellular calcium levels, and translocated into the nucleus, resulting in transcriptional activation. Calcineurin dephosphorylates various target proteins and regulates their functions. However, the regulation of NFAT degradation is largely unknown, and it is unclear whether calcineurin contributes to the stability of NFAT. We investigated the effect of calcineurin inhibition on NFAT protein stability and found that the dephosphorylation of NFAT by calcineurin promotes the NFAT stabilization, whereas calcineurin mutant that is defective in phosphatase activity was unable to stabilize NFAT. Increased intracellular calcium ion concentration, which is essential for calcineurin activation, also induced NFAT stability. In addition, we identified S-phase kinase associated protein 2 (Skp2), an F-box protein of the SCF ubiquitin ligase complex, as a factor mediating degradation of NFAT when calcineurin was depleted. In summary, these findings revealed that the dephosphorylation of NFAT by calcineurin protects NFAT from degradation by Skp2 and promotes its protein stability. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that mediate repression of target genes by trimethylation of Lys27 in histone 3 (H3K27me3). Given the reported roles of EZH2 in cancer, it is perhaps not surprising that targeting EZH2 in cancer therapy has become a hot research topic. Indeed, different types of EZH2 inhibitors are currently under development and are being evaluated by clinical trials. Recently, Murashima et al. identified NPD13668, a novel EZH2 inhibitor, by using a cell-based high-throughput screening assay. NPD13668 inhibited EZH2 methyltransferase activity, and repressed cell growth in multiple cancer cell lines, indicating a potential role for this compound in cancer treatment. In this review, we will focus on the current knowledge regarding the biological significance of PRC2 and H3K27me, and the recent advances in developing and testing drugs that target PRC2. [ABSTRACT FROM AUTHOR]