title: Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis.
abstract: Tumors from patients with high-grade aggressive prostate cancer (PCa) exhibit increased expression of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines. Despite the association between MAOA and aggressive PCa, it is unclear how MAOA promotes PCa progression. Here, we found that MAOA functions to induce epithelial-to-mesenchymal transition (EMT) and stabilize the transcription factor HIF1α, which mediates hypoxia through an elevation of ROS, thus enhancing growth, invasiveness, and metastasis of PCa cells. Knockdown and overexpression of MAOA in human PCa cell lines indicated that MAOA induces EMT through activation of VEGF and its coreceptor neuropilin-1. MAOA-dependent activation of neuropilin-1 promoted AKT/FOXO1/TWIST1 signaling, allowing FOXO1 binding at the TWIST1 promoter. Importantly, the MAOA-dependent HIF1α/VEGF-A/FOXO1/TWIST1 pathway was activated in high-grade PCa specimens, and knockdown of MAOA reduced or even eliminated prostate tumor growth and metastasis in PCa xenograft mouse models. Pharmacological inhibition of MAOA activity also reduced PCa xenograft growth in mice. Moreover, high MAOA expression in PCa tissues correlated with worse clinical outcomes in PCa patients. These findings collectively characterize the contribution of MAOA in PCa pathogenesis and suggest that MAOA has potential as a therapeutic target in PCa.
authors.forename: Jason Boyang
authors.initials: JB
authors.lastname: Wu
authors.forename: Chen
authors.initials: C
authors.lastname: Shao
authors.forename: Xiangyan
authors.initials: X
authors.lastname: Li
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Li
authors.forename: Peizhen
authors.initials: P
authors.lastname: Hu
authors.forename: Changhong
authors.initials: C
authors.lastname: Shi
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.forename: Chun-Peng
authors.initials: CP
authors.lastname: Liao
authors.forename: Bangyan L
authors.initials: BL
authors.lastname: Stiles
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D008954:Models, Biological; D008995:Monoamine Oxidase / Q000235:genetics* / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000235:genetics; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human