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Clin Epigenetics. 2016 Feb 12;8:16. doi: 10.1186/s13148-016-0182-9. eCollection 2016.

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

Author information

1
Department 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.
2
Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada ; Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, British Columbia V5Z 1M9 Canada ; Department of Life, Health, and Chemical Sciences, The Open University, Milton Keynes, MK7 6BH UK.
3
Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada ; Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, British Columbia V5Z 1M9 Canada.
4
Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada.
5
Department of Computer Science, Faculty of Science, University of British Columbia, 2366 Main Mall, Vancouver, British Columbia V6T 1Z4 Canada ; Department of Molecular Oncology, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada.
6
Genetics Unit, Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada.
7
Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, British Columbia V5Z 1M9 Canada ; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9 Canada.
8
Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada ; Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, British Columbia V5Z 1M9 Canada ; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9 Canada.
9
Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3 Canada ; Department of Surgery, University of British Columbia, 910 W 10th Avenue, Vancouver, British Columbia V5Z 4E3 Canada.

Abstract

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.

KEYWORDS:

CBX2; Castration-resistant prostate cancer; Epigenetics; Metastatic prostate cancer; Polycomb

PMID:
26877821
PMCID:
PMC4751702
DOI:
10.1186/s13148-016-0182-9
[Indexed for MEDLINE]
Free PMC Article

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