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Identification of the Polycomb protein CBX2 as a potential drug target in advanced prostate cancer and beyond

University of British Columbia

Globally, prostate cancer (PCa) represents the most commonly diagnosed cancer in men. While localized PCa can often be cured, all patients with metastatic disease inevitably develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). Increasing evidence suggests that epigenetic alterations involving the Polycomb Group (PcG) family drive PCa progression. Although the PcG protein CBX2 is required for prostate development, its implication in human cancer remains unexplored. I therefore hypothesized that CBX2 may become deregulated during PCa progression and induce transcriptional programs promoting PCa aggressiveness. Using patient-derived xenografts and clinical datasets, I have explored the epigenetic landscape of advanced PCa and identified the Polycomb Group protein and epigenetic reader CBX2 as a potential drug target. First, CBX2 was significantly up-regulated in metastatic and castration-resistant PCa tissues. Furthermore, CBX2 overexpression predicted lower overall survival and correlated with numerous adverse prognostic factors. In addition, CBX2 depletion induced proliferation arrest and apoptosis in metastatic PCa cell lines, implying that CBX2 is required for PCa cell survival. Microarray analysis conducted after CBX2 silencing revealed that CBX2 regulates many genes controlling cellular proliferation and differentiation. Given the rising incidence of NEPC in advanced PCa, I analyzed whether CBX2 was also involved in NEPC pathogenesis. Strikingly, CBX2 was consistently the most highly up-regulated epigenetic regulator across multiple clinical and xenograft tumor tissues. Furthermore, I derived a list of 185 genes down-regulated in NEPC that was preferentially enriched in PcG target genes and predicted poor clinical outcome, in line with a critical function for CBX2 in late-stage PCa. Since CBX2 has never been linked to human cancers, I conducted a comprehensive meta-analysis of CBX2 across many tumor types using previously published clinical data. Strikingly, these studies demonstrated that the CBX2 locus is rarely inactivated or down-regulated. In contrast, CBX2 was frequently amplified and over-expressed in many common tumors, where it correlated with metastatic dissemination and poor clinical outcome. Overall, this work identifies CBX2 as novel epigenetic driver of cancer progression and investigates the therapeutic potential of CBX2 in advanced solid malignancies.

Text

2015-08-17

Attribution 2.5 Canada

http://hdl.handle.net/2429/54471

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by/2.5/ca/