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

// Youhong Liu 1, 2, * , Yijun Liu 1, 2, * , Bowen Yuan 1, 2 , Linglong Yin 1, 2 , Yuchong Peng 1, 2 , Xiaohui Yu 1, 2 , Weibing Zhou 3 , Zhicheng Gong 4 , Jianye Liu 5, 6 , Leye He 5, 6 , Xiong Li 1, 2, 6 1 Center for Molecular Medicine, Xiangya Hospital, Central South University, China 2 Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, China 3 Department of Oncology, Xiangya Hospital, Central South University, China 4 Department of Pharmacy, Xiangya Hospital, Central South University, China 5 Department of Urology, The Third Xiangya Hospital, Central South University, China 6 Research Institute of Prostate Diseases, Central South University, China * These authors equally contributed to this paper Correspondence to: Xiong Li, email: lixiongxiangya@csu.edu.cn Keywords: PSA, FOXM1, gene transcription, androgen receptor, prostate cancer Received: November 11, 2016      Accepted: January 09, 2017      Published: February 09, 2017 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.