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

• DOI: 10.1038/onc.2017.330
• Publication Date: 2017-09-19T10:44:04Z
• Authors: S Stelloo; E Nevedomskaya; Y Kim; L Hoekman; O B Bleijerveld; T Mirza; L F A Wessels; W M van Weerden; A F M Altelaar; A M Bergman; W Zwart
• Keywords: Hepatocyte Nuclear Factor 3-alpha; Male; Proteomics; 0301 basic medicine; Carcinogenesis; Mice, Nude; Epigenesis, Genetic; Mice; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Cell Line, Tumor; Taverne; EMC MM-03-49-01; Journal Article; Animals; Humans; Cell Proliferation; Homeodomain Proteins; Gene Expression Profiling; Prostate; Prostatic Neoplasms; Genomics; 3. Good health; Gene Expression Regulation, Neoplastic; Cell Transformation, Neoplastic; Receptors, Androgen; Androgens

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.