Abstract
Androgen/AR is the primary contributor to prostate cancer (PCa) progression by regulating Prostate Specific Antigen (PSA) gene transcription. The disease inevitably evolves to androgen-independent (AI) status. Other mechanisms by which PSA is regulated and develops to AI have not yet been fully determined. FOXM1 is a cell proliferation-specific transcription factor highly expressed in PCa cells compared to non-malignant prostate epithelial cells, suggesting that the aberrant overexpression of FOXM1 contributes to PCa development. In addition to regulating AR gene transcription and cell cycle-regulatory genes, FOXM1 selectively regulates the gene transcription of KLK2 and PSA, typical androgen responsive genes. Screening the potential FOXM1-binding sites by ChIP-PCR, we found that FOXM1 directly binds to the FHK binding motifs in the PSA promoter/enhancer regions. AI C4-2 cells have more FOXM1 binding sites than androgen dependent LNCaP cells. The depletion of FOXM1 by small molecular inhibitors significantly improves the suppression of PSA gene transcription by the anti-AR agent Cadosax. This is the first report showing that FOXM1 promotes PCa progression by regulating PSA gene transcription, particularly in AI PCa cells. The combination of anti-AR agents and FOXM1 inhibitors has the potential to greatly improve therapy for late-stage PCa patients by suppressing PSA levels.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer death in males in the United States [1]
Since androgen/androgen receptor (AR) is critical in the development of prostate cancer (PCa), we investigated the roles of FOXM1 in the transcription regulation of cell cycle regulatory genes and androgen responsive genes
We tested how Prostate Specific Antigen (PSA) gene was regulated by FOXM1, a cell proliferation-specific transcription factor, in addition to androgen/AR in both androgendependent and androgen-independent PCa cells
Summary
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer death in males in the United States [1]. PSA, a widely used marker for PCa early screening and for assessing patient therapeutic response, is not sufficient to predict tumor aggressiveness, resulting in over-diagnosis and over-treatment [3]. Androgen/androgen receptor (AR), the primary regulator of PSA, is essential for PCa initiation and progression. Androgen deprivation therapies (ADT) using luteinizing hormone-releasing hormone agonists or antagonists, such as flutamide or casodex, decrease PSA levels and slow disease progression [4, 5] but tumor regression is temporary, and PCa evolves to androgenindependent (AI) status. PCa is typically refractory to current treatments at this stage and the disease becomes lethal
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