FOXM1 promotes the progression of prostate cancer by regulating PSA gene transcription.

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.

• Authors: Youhong Liu, Yijun Liu, Bowen Yuan, Linglong Yin, Yuchong Peng, Xiaohui Yu, Weibing Zhou, Zhicheng Gong, Jianye Liu, Leye He, Xiong Li
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 10 Pg. 17027-17037 (Mar 07 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28199985 (Publication Type: Journal Article)

Chemical References

• FOXM1 protein, human
• Forkhead Box Protein M1
• Receptors, Androgen
• KLK2 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• Base Sequence
• Binding Sites (genetics)
• Cell Line
• Cell Line, Tumor
• Disease Progression
• Forkhead Box Protein M1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Kallikreins (genetics, metabolism)
• Male
• Promoter Regions, Genetic (genetics)
• Prostate-Specific Antigen (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Binding
• RNA Interference
• Receptors, Androgen (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription, Genetic