Luciferase Reporter Cell Line - MyC-CaP

PRC2/EZH2 inhibitors (PRC2i/EZH2i) hold great promise for the treatment of advanced cancers, including metastatic prostate cancer. Here, researchers reveal that PRC2i/EZH2i-whether used alone or in combination with androgen receptor (AR) inhibitors-induce a variety of cell state programs (CSPs). Although these therapies exert only a modest inhibitory effect on tumor growth, they paradoxically lead to enhanced tumor cell invasion, metastasis, and resistance to other therapeutic agents. Contrary to current prevailing paradigms, comprehensive and integrated genomic and epigenomic analyses of patient-derived xenograft (PDX) models and clinical tumors demonstrate that PRC2/EZH2 suppresses the expression of CSP-associated genes by maintaining chromatin bivalency. Both hyperactive Wnt/β-catenin signaling and inhibitors targeting Polycomb Repressive Complex 2/Enhancer of Zeste Homolog 2 (PRC2/EZH2) and AR alter the bivalent state of chromatin by antagonizing PRC2 and activating MLL2/KMT2B in a feed-forward manner. Unexpectedly, the circadian rhythm regulator REV-ERBα remodels β-catenin function, thereby promoting the resolution of chromatin bivalency and the expression of CSP-associated genes. Dual targeting of Wnt/β-catenin and EZH2 effectively eliminates various aberrant cell states by restoring chromatin bivalency and potently suppresses tumor growth. These findings not only provide unexpected new insights into the roles of chromatin bivalency and circadian dysregulation in governing cell state diversity but also chart new directions for PRC2/EZH2-targeted therapeutic strategies against advanced malignancies.

To better understand the efficacy of combination therapy involving PRC2 inhibitors (PRC2i) and AR inhibitors (ARSi), researchers first evaluated the effects of the EZH2 inhibitors tazemetostat/EPZ6438 (Taz) and mevrometostat/PF-06821497 (Mev), the EED inhibitor EED226 (EEDi), and the AR antagonist enzalutamide (Enz) on cell viability and tumor growth across various prostate cancer (PCa) models. For orthotopic implantation within the prostate, they implanted luciferase-expressing Myc-CaP cells (Myc-CaP-Luc). Notably, Taz and its combination with Enz did not completely block tumor growth, as significant tumor growth persisted in both the syngeneic and patient-derived xenograft (PDX) models (Figure 1A-C). Of particular importance, this combination therapy significantly promoted tumor metastasis to the liver (Figure 1A). Treatment with EZH2 or EED inhibitors alone significantly increased the population of cancer stem cells (CSCs). This finding was corroborated by tumor sphere formation assays and flow cytometry analyses targeting CSC markers. Furthermore, this treatment greatly enhanced cellular migration and invasion capabilities. Treatment in combination with Enz resulted in even more pronounced manifestations of these effects (Figure 1D and E). These experimental results align closely with the tumor metastasis-promoting effects observed with the combination therapy.

Figure 1. Therapeutic targeting of PRC2/EZH2 and the AR increases drug resistance and promotes tumor metastasis. (Yang Y, et al., 2026)