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Suppression of Prostate Tumor Growth by U19, a Novel Testosterone-regulated Apoptosis Inducer¹

Departments of Urology [W. X., Q. Z., F. J., J. M. K., Z. W.], Molecular Pharmacology and Biological Chemistry [Z. W.], and Pathology [M. P.], The Robert H. Lurie Comprehensive Cancer Center [M. P., J. M. K., Z. W.], Northwestern University Medical School, Chicago, Illinois 60611

Androgens control prostate homeostasis and regulate androgen response genes. Here, we report the identification and characterization of U19, a novel testosterone-regulated apoptosis inducer with tumor suppressive activity. U19 is an evolutionarily conserved protein expressed in many human tissues, with the most abundant expression in the prostate, bone marrow, kidney, and lymph nodes. Overexpression of U19 in 12 surveyed cell lines induced apoptosis, and new protein synthesis is required for apoptosis induction. Expression of U19 in xenograft prostate tumors markedly induced apoptosis and inhibited tumor growth in vivo. Consistent with its tumor-suppressive role, U19 down-regulation was observed in all of the surveyed prostate cancer cell lines and in 19 of 23 clinical human prostate tumor specimens. Loss of heterozygosity analysis revealed U19 allelic loss in 19 of the 23 specimens. Furthermore, two of the specimens had homozygous U19 deletions, and one specimen had hypermethylated U19 promoter, indicating that U19 can be inactivated genetically or epigenetically. These observations suggest that U19 is growth inhibitory and tumor suppressive and that the disruption of androgen-dependent growth inhibition via U19 down-regulation is commonly associated with prostate cancer progression.

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