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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]

UHRF1 (Ubiquitin‐like with PHD and ring finger domains 1) regulates DNA methylation and histone modifications and plays a key role in cell proliferation and the DNA damage response. However, the function of UHRF2, a paralog of UHRF1, in the DNA damage response remains largely unknown. Here, we show that UHRF2 is essential for maintaining cell viability after UV irradiation, as well as for the proliferation of cancer cells. UHRF2 was found to physically interact with ATR in a DNA damage‐dependent manner through UHRF2's TTD domain. In addition, phosphorylation of threonine at position 1989, which is required for UV‐induced activation of ATR, was impaired in cells depleted of UHRF2, suggesting that UHRF2 is essential in ATR activation. In conclusion, these results suggest a new regulatory mechanism of ATR activation mediated by UHRF2. [ABSTRACT FROM AUTHOR]

c-Myc, a transcription factor, induces cell proliferation and is often aberrantly or highly expressed in cancers. However, molecular mechanisms underlying this aberrantly high expression remain unclear. Here, we found that intracellular Ca2+ concentration regulates c-Myc oncoprotein stability. We identified that calcineurin, a Ca2+-dependent protein phosphatase, is a positive regulator of c-Myc expression. Calcineurin depletion suppresses c-Myc targeted gene expression and c-Myc degradation. Calcineurin directly dephosphorylates Thr58 and Ser62 in c-Myc, which inhibit binding to the ubiquitin ligase Fbxw7. Mutations within the autoinhibitory domain of calcineurin, most frequently observed in cancer, may increase phosphatase activity, increasing c-Myc transcriptional activity in turn. Notably, calcineurin inhibition with FK506 decreased c-Myc expression with enhanced Thr58 and Ser62 phosphorylation in a mouse xenograft model. Thus, calcineurin can stabilize c-Myc, promoting tumor progression. Therefore, we propose that Ca2+ signaling dysfunction affects cancer-cell proliferation via increased c-Myc stability and that calcineurin inhibition could be a new therapeutic target of c-Myc-overexpressing cancers. [ABSTRACT FROM AUTHOR]

c-Myc, a transcription factor, induces cell proliferation and is often aberrantly or highly expressed in cancers. However, molecular mechanisms underlying this aberrantly high expression remain unclear. Here, we found that intracellular Ca2+ concentration regulates c-Myc oncoprotein stability. We identified that calcineurin, a Ca2+-dependent protein phosphatase, is a positive regulator of c-Myc expression. Calcineurin depletion suppresses c-Myc targeted gene expression and c-Myc degradation. Calcineurin directly dephosphorylates Thr58 and Ser62 in c-Myc, which inhibit binding to the ubiquitin ligase Fbxw7. Mutations within the autoinhibitory domain of calcineurin, most frequently observed in cancer, may increase phosphatase activity, increasing c-Myc transcriptional activity in turn. Notably, calcineurin inhibition with FK506 decreased c-Myc expression with enhanced Thr58 and Ser62 phosphorylation in a mouse xenograft model. Thus, calcineurin can stabilize c-Myc, promoting tumor progression. Therefore, we propose that Ca2+ signaling dysfunction affects cancer-cell proliferation via increased c-Myc stability and that calcineurin inhibition could be a new therapeutic target of c-Myc-overexpressing cancers. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) is highly expressed or abnormally activated in several types of cancers, such as lung and colorectal cancers. Inhibitors that suppress the tyrosine kinase activity of EGFR have been used in the treatment of lung cancer. However, resistance to these inhibitors has become an issue in cancer treatment, and the development of new therapies that inhibit EGFR is desired. We found that calcineurin, a Ca2+/calmodulin-activated serine/threonine phosphatase, is a novel regulator of EGFR. Inhibition of calcineurin by FK506 treatment or calcineurin depletion promoted EGFR degradation in cancer cells. In addition, we found that calcineurin dephosphorylates EGFR at serine (S)1046/1047, which in turn stabilizes EGFR. Furthermore, in human colon cancer cells transplanted into mice, the inhibition of calcineurin by FK506 decreased EGFR expression. These results indicate that calcineurin stabilizes EGFR by dephosphorylating S1046/1047 and promotes tumor growth. These findings suggest that calcineurin may be a new therapeutic target for cancers with high EGFR expression or activation. • Calcineurin depletion reduces EGFR expression and attenuates EGFR signaling. • Calcineurin increases EGFR stability via dephosphorylation at Ser1046/1047. • Inhibiting lysosome function inhibits EGFR degradation in FK506-treated cells. • Calcineurin inhibition suppresses EGFR expression in vivo. [ABSTRACT FROM AUTHOR]

The Calcineurin/NFAT (nuclear factor of activated T cells) pathway plays an essential role in the tumorigenic and metastatic properties in breast cancer. The molecular mechanism of the antiproliferative effect of calcineurin inhibition, however, is poorly understood. We found that calcineurin inhibition delayed cell cycle progression at G1/S, and promoted cyclin D1 degradation by inhibiting dephosphorylation at T286. Importantly, overexpression of cyclin D1 partially rescued delayed G1/S progression, thereby revealing cyclin D1 as a key factor downstream of calcineurin inhibition. Cyclin D1 upregulation is observed in human invasive breast cancers, and our findings indicate that dysregulation of T286 phosphorylation could play a role in this phenomenon. We therefore propose that targeting site specific phosphorylation of cyclin D1 could be a potential strategy for clinical intervention of invasive breast cancer. [ABSTRACT FROM AUTHOR]