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  • Last we demonstrate that the

    2021-12-01

    Last, we demonstrate that the role of EZH2 as a transcriptional activator, with AR being a key target, coexists with its conventional catalytic role in gene repression and plays important oncogenic functions in AR-driven PCa (Figure 7F). Enzymatic EZH2 inhibitors such as EPZ and GSK126, although effective in blocking the enzymatic roles of EZH2, are unable to suppress EZH2-mediated activation of the AR. Instead, they inadvertently increase AR expression, as demonstrated in our data and in a recent report (Ku et al., 2017), which may account for their failure in suppressing AR-positive PCa, as noted previously (Dardenne et al., 2016) and also as observed in our study. In addition, these studies have found that enzymatic EZH2 inhibitors are much more effective in AR-negative NEPC cells, which is consistent with our model. Moreover, understanding the molecular mechanisms of EZH2 functions in PCa allowed us to propose a strategy for the use of these clinically available enzymatic EZH2 inhibitors, through combination with AR antagonist, in a subtype of PCa (i.e., CRPC) that is driven by AR and expresses high levels of EZH2. We understand that the AR antagonist will target all ARs, induced either by EZH2 or through other mechanisms such as AR gene amplification. Nevertheless, it 2-NBDG synthesis is legitimate and a common practice to target a key downstream pathway when the upstream regulator itself is not yet targetable. Our results suggest that compounds capable of degrading EZH2 protein, similar to EZH2 knockdown, might greatly outperform enzymatic EZH2 inhibitors and would have higher specificity in blocking the dual roles of EZH2. It would be important to develop such small-molecule inhibitors in future studies. In summary, our study reports a non-catalytic role of EZH2 in transcriptional activation and provides compelling preclinical data to support clinical applications of combinatorial Enz and EPZ treatment in CRPC.
    STAR★Methods
    Acknowledgments We thank Dr. Ming Hu (Cleveland Clinic) for discussions regarding statistical analysis and Bin Zheng and Galina Gritsina for technical help. This work was supported in part by National Cancer Institute R01CA172384 (to J.Y.), P50CA180995 (pilot project, to J.Y.), and R50CA211271 (to J.C.Z.); American Cancer Society Research Scholar Award RSG-12-085-01 (to J.Y.); Department of Defense PC160328 (to J.Y.); and an institutional Ruth L. Kirschstein National Research Service award from the National Institute of Diabetes and Digestive and Kidney Diseases T32 DK007169 (to J.K.).
    Introduction EZH2, the catalytic component of the Polycomb repressive complex 2 (PRC2), silences gene transcription by methylating histone H3 at lysine 27 (Czermin et al., 2002, Müller et al., 2002). EZH2 is mutated or highly expressed in many types of cancer, including lymphoma (Morin et al., 2010), melanoma (Bachmann et al., 2006), prostate cancer (Varambally et al., 2002), ovarian cancer (Lu et al., 2010), and breast cancer (Kleer et al., 2-NBDG synthesis 2003). Experimentally, overexpression of EZH2 has been shown to promote cell proliferation, tumorigenesis, and metastasis (Bracken et al., 2003, Chang et al., 2011, Kleer et al., 2003, Min et al., 2010). Conversely, depletion of EZH2 leads to growth inhibition. For example, knockdown of EZH2 in a triple-negative breast cancer (TNBC) cell line, MDA-MB-231, suppressed tumor growth and metastasis in xenograft models (Gonzalez et al., 2009, Moore et al., 2013). The cancer-promoting function of EZH2 is also supported by genetically engineered mouse models. For instance, transgenic overexpression of EZH2 or its gain-of-function mutant in mice led to hyperplasia and accelerated Myc- or Bcl2-induced lymphomagenesis (Béguelin et al., 2013, Berg et al., 2014) and Erbb2-induced mammary tumorigenesis (Gonzalez et al., 2014, Li et al., 2009). Moreover, expression of a lymphoma-derived hyperactivating mutant of EZH2 from the endogenous locus in mouse B cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively (Souroullas et al., 2016). These findings have prompted intensive efforts to develop EZH2 inhibitors.