Angiomotin regulates prostate cancer cell proliferation by signaling through the Hippo-YAP pathway
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Hao Zeng1, Angelica Ortiz2,3,*, Peng-Fei Shen1,*, Chien-Jui Cheng4,5, Yu-Chen Lee2, Guoyu Yu2, Song-Chang Lin2, Chad J. Creighton6, Li-Yuan Yu-Lee7, Sue-Hwa Lin2,3,8
1Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
2Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
3The University of Texas Graduate School of Biomedical Sciences at Houston, Texas, USA
4Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
5Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan
6Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
7Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
8Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
*These authors have contributed equally to this work
Hao Zeng, email: [email protected], [email protected]
Sue-Hwa Lin, email: [email protected]
Keywords: angiomotin, Hippo pathway, YAP, BMP4, proliferation
Abbreviations: Angiomotin (AMOT), neurofibromatosis type 2 (NF2), prostate cancer (PCa)
Received: October 11, 2016 Accepted: December 13, 2016 Published: December 29, 2016
Angiomotin (AMOT) is a family of proteins found to be a component of the apical junctional complex of vertebrate epithelial cells and is recently found to play important roles in neurofibromatosis type 2 (NF-2). Whether AMOT plays a role in prostate cancer (PCa) is unknown. AMOT is expressed as two isoforms, AMOTp80 and AMOTp130, which has a 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a low to undetectable level in PC3, DU145, and BPH1 cells. Further study showed that AMOTp130 and AMOTp80 have distinct functions in PCa cells. We found that AMOTp80, but not AMOT p130, functioned as a tumor promoter by enhancing PCa cell proliferation. Mechanistic studies showed that AMOTp80 signaled through the Hippo pathway by promoting nuclear translocation of YAP, resulting in an increased expression of YAP target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated cell proliferation. Together, this study reveals a novel mechanism whereby the AMOTp80-Merlin-MST1-LATS-YAP-BMP4 pathway leads to AMOTp80-induced tumor cell proliferation.
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