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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Samikshan Dutta - , University of Nebraska Medical Center (Author)
  • Navatha Shree Polavaram - , University of Nebraska Medical Center (Author)
  • Ridwan Islam - , University of Nebraska Medical Center (Author)
  • Sreyashi Bhattacharya - , University of Nebraska Medical Center (Author)
  • Sanika Bodas - , University of Nebraska Medical Center (Author)
  • Thomas Mayr - , University of Bonn (Author)
  • Sohini Roy - , University of Nebraska Medical Center (Author)
  • Sophie Alvarez Y. Albala - , University of Nebraska-Lincoln (Author)
  • Marieta I. Toma - , University of Bonn (Author)
  • Anza Darehshouri - , University of Texas Southwestern Medical Center (Author)
  • Angelika Borkowetz - , Department of Urology (Author)
  • Stefanie Conrad - , Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden (Author)
  • Susanne Fuessel - , Department of Urology (Author)
  • Manfred Wirth - , Department of Urology (Author)
  • Gustavo B Baretton - , Institute of Pathology, University Cancer Centre Dresden, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK) Partner Site Dresden (Author)
  • Lorenz C. Hofbauer - , Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK) Partner Site Dresden (Author)
  • Paramita Ghosh - , University of California at Davis (Author)
  • Kenneth J. Pienta - , Johns Hopkins Medicine (Author)
  • David L. Klinkebiel - , University of Nebraska Medical Center (Author)
  • Surinder K. Batra - , University of Nebraska Medical Center (Author)
  • Michael H. Muders - , University of Bonn (Author)
  • Kaustubh Datta - , University of Nebraska Medical Center (Author)

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.

Details

Original languageEnglish
Pages (from-to)3747-3760
Number of pages14
JournalOncogene
Volume41
Issue number30
Publication statusPublished - Jul 2022
Peer-reviewedYes

External IDs

Scopus 85132795580
unpaywall 10.1038/s41388-022-02382-y
ORCID /0000-0002-8691-8423/work/142236003
ORCID /0000-0001-9345-026X/work/150328895

Keywords

Sustainable Development Goals

Keywords

  • Androgens/pharmacology, Cell Line, Tumor, Humans, Male, Neuropilin-2/genetics, Prostatic Neoplasms, Castration-Resistant/metabolism, Receptors, Androgen/genetics, Signal Transduction

Library keywords