Aberrant transcriptional activity of androgen receptor (AR) is one of the dominant mechanisms for developing of castration-resistant prostate cancer (CRPC). Analyzing AR-transcriptional complex related to CRPC is therefore important towards understanding the mechanism of therapy resistance. While studying its mechanism, we observed that a transmembrane protein called neuropilin-2 (NRP2) plays a contributory role in forming a novel AR-transcriptional complex containing nuclear pore proteins. Using immunogold electron microscopy, high-resolution confocal microscopy, chromatin immunoprecipitation, proteomics, and other biochemical techniques, we delineated the molecular mechanism of how a specific splice variant of NRP2 becomes sumoylated upon ligand stimulation and translocates to the inner nuclear membrane. This splice variant of NRP2 then stabilizes the complex between AR and nuclear pore proteins to promote CRPC specific gene expression. Both full-length and splice variants of AR have been identified in this specific transcriptional complex. In vitro cell line-based assays indicated that depletion of NRP2 not only destabilizes the AR-nuclear pore protein interaction but also inhibits the transcriptional activities of AR. Using an in vivo bone metastasis model, we showed that the inhibition of NRP2 led to the sensitization of CRPC cells toward established anti-AR therapies such as enzalutamide. Overall, our finding emphasize the importance of combinatorial inhibition of NRP2 and AR as an effective therapeutic strategy against treatment refractory prostate cancer.
Oncogene. 2022 Jun 27 [Epub ahead of print]
Samikshan Dutta, Navatha Shree Polavaram, Ridwan Islam, Sreyashi Bhattacharya, Sanika Bodas, Thomas Mayr, Sohini Roy, Sophie Alvarez Y Albala, Marieta I Toma, Anza Darehshouri, Angelika Borkowetz, Stefanie Conrad, Susanne Fuessel, Manfred Wirth, Gustavo B Baretton, Lorenz C Hofbauer, Paramita Ghosh, Kenneth J Pienta, David L Klinkebiel, Surinder K Batra, Michael H Muders, Kaustubh Datta
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. ., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Rudolf Becker Laboratory for Prostate Cancer Research, Medical Faculty, University of Bonn, Bonn, Germany., Department of Agronomy and Horticulture, University of Nebraska-Lincoln, Lincoln, NE, USA., Institute of Pathology, Medical Faculty, University of Bonn, Bonn, Germany., Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA., Department of Urology, Technische Universitaet Dresden, Dresden, Germany., Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universitaet Dresden, Dresden, Germany., Institute of Pathology, Technische Universitaet Dresden, Dresden, Germany., Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA., The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. .