Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer

Authors

Samikshan Dutta, University of Nebraska Medical CenterFollow
Navatha Shree Polavaram, University of Nebraska Medical Center
Ridwan Islam, University of Nebraska Medical Center
Sreyashi Bhattacharya, University of Nebraska Medical Center
Sanika Bodas, University of Nebraska Medical Center
Thomas Mayr, University of Bonn, Technische Universitaet Dresden
Sohini Roy, University of Nebraska Medical Center
Sophie Alvarez, University of Nebraska-LincolnFollow
Marieta I. Toma, University of Bonn, Technische Universitaet Dresden
Anza Darehshouri, UT Southwestern Medical Center
Angelika Borkowetz, Technische Universitaet Dresden
Stefanie Conrad, Technische Universitaet Dresden,
Susanne Fuessel, Technische Universitaet Dresden
Manfred Wirth, Technische Universitaet Dresden
Gustavo B. Baretton, Technische Universitaet Dresden, German Cancer Consortium (DKTK)
Paramita Ghosh, University of California Davis
Kenneth J. Pienta, Johns Hopkins University School of Medicine
David L. Klinkebiel, University of Nebraska Medical Center
Surinder K. Batra, University of Nebraska Medical CenterFollow
Michael H. Muders, University of Bonn, Technische Universitaet Dresden
Kaustubh Datta, University of Nebraska Medical CenterFollow

Date of this Version

7-2022

Citation

Oncogene. 2022 July ; 41(30): 3747–3760. doi:10.1038/s41388-022-02382-y.

Comments

HHS Public Access

Abstract

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.