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Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis

Abstract

Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners. Interestingly, three major subgroups of genomic subcomplexes were identified, where selective gain of function for AR genomic action in tumorigenesis was found, dictated by FOXA1 and HOXB13. In summary, by combining proteomic and genomic approaches we reveal subclasses of AR transcriptional complexes, differentiating normal AR behavior from the oncogenic state. In this process, the expression of AR interactors has key roles by reprogramming the AR cistrome and interactome in a genomic location-specific manner.

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Acknowledgements

We thank the NKI Genomics Core Facility for Illumina sequencing and bioinformatic support. SS is supported by Movember (NKI01). We thank Corrina MA de Ridder for dedicated maintenance and biobanking of the PDX models. WZ is supported by a KWF Dutch Cancer Society/Alpe d’HuZes Bas Mulder Award (NKI 2014-6711) and a VIDI grant (016.156.401) from The Netherlands Organisation for Scientific Research (NWO). This work is further supported by NWO as part of the National Roadmap Large-scale Research Facilities of the Netherlands, Proteins@Work (184.032.201) to OBB and AFMA and a VIDI grant (723.012.102) to AFMA.

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Correspondence to S Stelloo or W Zwart.

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Stelloo, S., Nevedomskaya, E., Kim, Y. et al. Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis. Oncogene 37, 313–322 (2018). https://doi.org/10.1038/onc.2017.330

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