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

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. BatraMichael H. Muders, Kaustubh Datta

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3747-3760
Number of pages14
JournalOncogene
Volume41
Issue number30
DOIs
StatePublished - Jul 22 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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