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Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer
Pier-Luc Clermont1, Francesco Crea2, Yan Ting Chiang3
1Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada ; Faculty of Medicine, MD Program, Université Laval, 1050, avenue de la Médecine, Québec, QC G1V 0A6 Canada.
Background:
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.
Results:
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.
Conclusions:
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.
Insights
Targeting CBX2, a polycomb group protein, shows promise for treating lethal prostate cancer (PCa). Inhibiting CBX2 triggers cancer cell death and may offer new therapeutic strategies for castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Localized prostate cancer (PCa) is curable, but metastatic disease progresses to lethal castration-resistant prostate cancer (CRPC).
- Aberrant epigenetic repression by polycomb group (PcG) complexes is implicated in PCa progression.
- PcG complexes represent potential therapeutic targets for advanced PCa.
Purpose of the Study:
- To identify novel epigenetic drivers of CRPC.
- To investigate the role of PcG proteins in advanced PCa.
- To evaluate CBX2 as a potential therapeutic target in CRPC.
Main Methods:
- Analysis of PcG member molecular profiles in patient-derived xenografts and clinical samples.
- Assessment of CBX2 expression correlation with clinical outcomes in PCa cohorts.
- In vitro studies involving CBX2 depletion in metastatic PCa cell lines, including microarray analysis and apoptosis assays.
Main Results:
- CBX2, a PcG protein and methyl-lysine reader, is recurrently up-regulated in metastatic CRPC.
- Elevated CBX2 expression correlates with poor clinical outcomes in PCa patients.
- CBX2 depletion reduces cell viability and induces apoptosis via caspase 3.
- CBX2 regulates key genes involved in cell proliferation and metastasis.
Conclusions:
- CBX2 inhibition induces cancer cell death in lethal CRPC.
- CBX2 is a promising therapeutic target for advanced prostate cancer.
- This study provides the first evidence for CBX2 as a druggable target in CRPC.
