SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

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Development of prostate cancer is a multistep process that involves the loss of tumor suppressor functions and activation of oncogenes. SPDEF transcription factor is expressed in normal prostate epithelium and its expression changes during prostate carcinogenesis (PCa). Since the role of SPDEF in PCa remains controversial, we generated transgenic mice with loss -⁠ and gain-of-function of SPDEF to demonstrate that SPDEF functions as a tumor suppressor in PCa. In animal models, the loss of SPDEF promoted PCa and increased the levels of Foxm1, a well-known oncogenic protein. Overexpression of SPDEF in prostate epithelium decreased PCa and reduced Foxm1 levels. Proliferation defects in SPDEF-containing tumor cells were corrected by re-expression of Foxm1, providing direct evidence that SPDEF inhibits tumor cell proliferation through Foxm1. We further showed that SPDEF directly bound to Foxm1 promoter and prevented its auto-regulatory activation. In prostate cancer patients, the low SPDEF and high Foxm1 were found in most aggressive prostate tumors that were associated with poor prognosis. The combined two-gene signature of low SPDEF and high Foxm1 was a strong predictor of survival in prostate cancer patients. The present study identified novel molecular mechanism of prostate cancer progression, providing a crosstalk between SPDEF tumor suppressor and Foxm1 oncogene.

Vyšlo v časopise: SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004656
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004656

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