Editors' ChoiceProstate Cancer

EZ(H2) Does It!

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Science Translational Medicine  10 Mar 2010:
Vol. 2, Issue 22, pp. 22ec37
DOI: 10.1126/scitranslmed.3001020

Nearly all prostate cancer deaths are due to metastases, yet little is known about why prostate cancer cells metastasize. One candidate marker of prostate cancer metastatic potential is the EZH2 histone methyltransferase, a chromatin-modifying enzyme that leads to reversible transcriptional repression of its target genes and is up-regulated in human prostate cancer. However, the biological role and clinical relevance of EZH2 in metastasis formation, and its specific target gene mediators, remained unclear.

Now, using normal and cancerous prostate cells in vitro and implanted orthotopically in mice prostates, Min et al. show that DAB2IP, an EZH2 target gene, is a metastasis and tumor suppressor. DAB2IP loss led to constitutive activation of two critical signaling pathways that it modulates, Ras and nuclear factor κB, and promoted metastasis. Overexpression of both EZH2 and DAB2IP in mice prostates abrogated the effect of increased metastatic potential and decreased survival in mice that were observed with overexpression of EZH2 alone. This indicates that DAB2IP is a critical EZH2 target gene involved in the development of prostate cancer aggressiveness and metastasis.

Given the reversibility of DAB2IP repression by EZH2, it is rational to test EZH2 inhibitors in patients whose prostate cancers harbor high levels of EZH2 and have lost expression of DAB2IP. For the 27,000 men who are predicted to die of prostate cancer this year and those who care for them, these agents to prevent metastases and improve survival—now in clinical development—cannot arrive soon enough.

J. Min et al., An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-κB. Nat. Med. 14 February 2010 (doi: 10.1038/nm2100). [Full Text]

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