Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer
| Autor: | Tianjie Pu, Tzu Ping Lin, Allen C. Gao, Boyang Jason Wu, Jing Wei, Lijuan Yin, Jingjing Li, Peng Duan, Jing Wang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Transcriptional Activation Cancer Research Mice SCID urologic and male genital diseases Article Mice Prostate cancer chemistry.chemical_compound Cell Line Tumor Nitriles Phenylthiohydantoin medicine Animals Humans Gene silencing Enzalutamide Gene Silencing Monoamine Oxidase Cell Nucleus Feedback Physiological biology Chemistry Apalutamide Computational Biology medicine.disease Hormones Androgen receptor Prostatic Neoplasms Castration-Resistant Darolutamide Oncology Receptors Androgen Benzamides Mutagenesis Site-Directed Cancer research biology.protein Monoamine oxidase A Androgen Response Element Neoplasm Transplantation Signal Transduction |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-21-0198 |
| Popis: | Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1–AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA–AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC. Significance: MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment. |
| Databáze: | OpenAIRE |
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