Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer

Pier-Luc Clermont, Francesco Crea, Yan Ting Chiang, Dong Lin, Amy Zhang, James Z. L. Wang, Abhijit Parolia, Rebecca Wu, Hui Xue, Yuwei Wang, Jiarui Ding, Kelsie L. Thu, Wan L. Lam, Sohrab P. Shah, Colin C. Collins, Yuzhuo Wang, Cheryl D. Helgason

While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis. Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.