Deleted in Breast Cancer 1, a Novel Androgen Receptor (AR) Coactivator That Promotes AR DNA-binding Activity (2009)

Androgen receptor (AR) plays a critical role in development and maintenance of male reproductive functions and the etiology of prostate cancer. As a ligand-regulated transcription factor, identification and characterization of AR coregulators are essential for understanding the molecular mechanisms underlying its diverse biological functions. Here we reported the identification of a novel AR coactivator, deleted in breast cancer 1 (DBC1), through a biochemical approach. DBC1 interacts with AR in a ligand-stimulated manner and facilitates AR transcriptional activation in transfected cells as well as in Xenopus oocytes. In in vitro gel shift experiments, recombinant DBC1 drastically enhanced AR DNA-binding activity. Expression of DBC1 also enhanced the binding of AR to chromatinized template in vivo, whereas knockdown of DBC1 impaired the binding of AR to endogenous prostate-specific antigen (PSA) gene in the prostate cancer cell line LNCaP. Thus, our data identify DBC1 as a novel AR coactivator. Androgen receptor (AR) plays a critical role in development and maintenance of male reproductive functions and the etiology of prostate cancer. As a ligand-regulated transcription factor, identification and characterization of AR coregulators are essential for understanding the molecular mechanisms underlying its diverse biological functions. Here we reported the identification of a novel AR coactivator, deleted in breast cancer 1 (DBC1), through a biochemical approach. DBC1 interacts with AR in a ligand-stimulated manner and facilitates AR transcriptional activation in transfected cells as well as in Xenopus oocytes. In in vitro gel shift experiments, recombinant DBC1 drastically enhanced AR DNA-binding activity. Expression of DBC1 also enhanced the binding of AR to chromatinized template in vivo, whereas knockdown of DBC1 impaired the binding of AR to endogenous prostate-specific antigen (PSA) gene in the prostate cancer cell line LNCaP. Thus, our data identify DBC1 as a novel AR coactivator. Androgen receptor (AR) 2The abbreviations used are: AR, androgen receptor; NR, nuclear receptor; LBD, ligand-binding domain; DBC1, deleted in breast cancer 1; aa, amino acid(s); GST, glutathione S-transferase; HA, hemagglutinin; DSP, dithiobis(succinimidyl propionate); MMTV, murine mammary tumor virus; siRNA, small interference RNA; RT, reverse transcription; ChIP, chromatin immunoprecipitation; IP, immunoprecipitation; LTR, long terminal repeat; ERα, estrogen receptor α. mediates the diverse biological functions of androgens, including development and maintenance of male reproductive functions and the etiology of prostate cancer (1Lee H.J. Chang C. Cell Mol. 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Chem. 1999; 274: 20229-20234Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar), ARA70 (22Yeh S. Chang C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5517-5521Crossref PubMed Scopus (534) Google Scholar), FHL2 (23Muller J.M. Isele U. Metzger E. Rempel A. Moser M. Pscherer A. Breyer T. Holubarsch C. Buettner R. Schule R. EMBO J. 2000; 19: 359-369Crossref PubMed Scopus (292) Google Scholar), and p44 (24Hosohata K. Li P. Hosohata Y. Qin J. Roeder R.G. Wang Z. Mol. Cell Biol. 2003; 23: 7019-7029Crossref PubMed Scopus (71) Google Scholar). Most of the cofactors are initially identified as interacting proteins for one or more NRs through yeast two-hybrid screenings using either NR LBDs or N-terminal domains as baits (9Onate S.A. Tsai S.Y. Tsai M.J. O'Malley B.W. Science. 1995; 270: 1354-1357Crossref PubMed Scopus (2075) Google Scholar, 10Voegel J.J. Heine M.J. Zechel C. Chambon P. Gronemeyer H. EMBO J. 1996; 15: 3667-3675Crossref PubMed Scopus (957) Google Scholar, 11Hong H. Kohli K. Trivedi A. Johnson D.L. Stallcup M.R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4948-4952Crossref PubMed Scopus (616) Google Scholar, 12Li H. Gomes P.J. Chen J.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8479-8484Crossref PubMed Scopus (507) Google Scholar, 13Chen H. Lin R.J. Schiltz R.L. Chakravarti D. Nash A. Nagy L. Privalsky M.L. Nakatani Y. Evans R.M. Cell. 1997; 90: 569-580Abstract Full Text Full Text PDF PubMed Scopus (1278) Google Scholar, 14Torchia J. Rose D.W. Inostroza J. Kamei Y. Westin S. Glass C.K. Rosenfeld M.G. Nature. 1997; 387: 677-684Crossref PubMed Scopus (1111) Google Scholar). However, biochemical approaches also play an important role in identification of NR cofactors. For example, the mediator complex, also known as TRAP and DRIP, was isolated as liganded thyroid hormone receptor and vitamin D receptor-associated protein complex, respectively (17Fondell J.D. Ge H. Roeder R.G. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8329-8333Crossref PubMed Scopus (468) Google Scholar, 25Rachez C. Suldan Z. Ward J. Chang C.P. Burakov D. Erdjument-Bromage H. Tempst P. Freedman L.P. Genes Dev. 1998; 12: 1787-1800Crossref PubMed Scopus (334) Google Scholar). The mediator complex is believed to coordinate with other cofactors to regulate the recruitment of RNA polymerase II. In this regard, biochemical purification of AR-associated protein complex(es) so far has resulted in only limited success. Only one protein, p44, was identified in a previous effort of biochemical purification of AR-associated proteins (24Hosohata K. Li P. Hosohata Y. Qin J. Roeder R.G. Wang Z. Mol. Cell Biol. 2003; 23: 7019-7029Crossref PubMed Scopus (71) Google Scholar). p44 was shown to enhance AR transcriptional activation both in vitro and in cells. This limited success may result from dissociation of AR-interacting proteins during cell lysis and/or purification process. In this study, we have employed a reversible cross-linking-based approach to capture AR·protein complexes in cells treated with or without synthetic AR ligand R1881. We then isolated AR complex(es) by immunoaffinity purification and identified AR-associated proteins by mass spectrometry. In addition to known coactivators such as the human BAF complex (SWI/SNF), we identified DBC1, a protein initially identified as “deleted in breast cancer 1” (26Hamaguchi M. Meth J.L. von Klitzing C. Wei W. Esposito D. Rodgers L. Walsh T. Welcsh P. King M.C. Wigler M.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13647-13652Crossref PubMed Scopus (189) Google Scholar, 27Sundararajan R. Chen G. Mukherjee C. White E. Oncogene. 2005; 24: 4908-4920Crossref PubMed Scopus (61) Google Scholar), as an AR-interacting protein. We demonstrated that DBC1 interacts with AR in a ligand-stimulated manner and facilitates AR transcriptional activity. The interaction between DBC1 and AR was mapped to the AR ligand binding domain and DBC1 N-terminal region. RNA interference experiments showed that DBC1 was required for optimal transcriptional activation of AR target in cells and binding of AR to the In recombinant DBC1 AR DNA-binding in gel shift our data have identified DBC1 as a novel AR coactivator. and and Z. Li J. J. Mol. 2002; PubMed Scopus Google Scholar). a cell line C-terminal AR, the AR was a containing DBC1 in was also the for of for of proteins in Xenopus J. EMBO J. 1997; PubMed Scopus Google Scholar), and for of recombinant DBC1 in cells. was by the whereas and For of DBC1 in we also and in to the using the and For in vitro DBC1 and the and proteins using a from by DNA DBC1 was by using recombinant The AR and from and from was from and as J. O'Malley B.W. J. Mol. Cell Biol. 2000; 20: PubMed Scopus Google Scholar). of the Cell cell line was using the cell line and from to the as J. Qin J. J. Mol. Cell Biol. PubMed Scopus Google Scholar). capture complexes in we of from is a proteins by in cells. The cell line was in the with for to in the was to the a of and the cells to The cells then treated without or with for to the of The cells by and with The with was in for was then the of and for to the The cells by and with and a of The for and for of AR from a Cell with 1 used for complex purification of of was to the and the was with for The with and with and The was for in The proteins with a with and for identification by mass as J. Chem. 1997; PubMed Scopus Google Scholar). and and as J. Qin J. J. Mol. Cell Biol. PubMed Scopus Google Scholar). of Xenopus and and of and DNA Xenopus as J. J. C. J. Mol. 2006; 20: PubMed Scopus Google Scholar). The of DNA for Xenopus was as J. Genes Dev. 1995; PubMed Scopus Google Scholar). used for using a In vitro was a of and in DNA was a of to the in was used to the of RNA in Xenopus oocytes. The used for has been J. J. C. J. Mol. 2006; 20: PubMed Scopus Google Scholar). The Xenopus was used as an in Cell and RNA in a Cell cells in with and cells the such a that cells by the of The of and DBC1 using to the the cells and for in the of The of was and the of the RNA knockdown was by using DBC1 For the and cells transfected with and the cells treated with for and the cells for the activity. was using and the for using of for of the and as and and and and The RNA was used as and to The DBC1 was from DBC1 in cells transfected with for as a The transfected cells treated with or without for for or for binding was by shift for AR the as Z. Li J. J. Mol. 2002; PubMed Scopus Google Scholar). The androgen was by using The binding also of AR and DBC1 from cells are in the of DNA binding 1 and of the binding for to addition of DNA binding in in and using Xenopus as J. J. C. J. Mol. 2006; 20: PubMed Scopus Google Scholar). The for of are and For in the cells in for with for The was as J. Mol. 2006; 20: PubMed Scopus Google Scholar). was in with the of 1 of The by The for for and for of for DNA from and for DNA from cells. of DBC1 as an AR-interacting AR cofactors through a biochemical we a cell line using the cell line and from and a in The of was by and by with or without AR synthetic ligand for The cells then treated with DSP, a reversible and for purification of and proteins using the complexes by a and by number of to with liganded and AR. in gel with and by mass spectrometry. The that the proteins that with liganded AR are and BAF proteins, the of human BAF or SWI/SNF complexes W. J. Y. S. C. M. J.L. EMBO J. 1996; 15: PubMed Scopus Google Scholar, W. Y. S. A. Genes Dev. 1996; PubMed Scopus Google Scholar). The interaction between AR and SWI/SNF has been reported K.A. Burd C.J. Williams E. Marshall T. Rosson G. Henry E. Weissman B. Knudsen K.E. Mol. Cell Biol. 2005; 25: 2200-2215Crossref PubMed Scopus (104) Google Scholar, Li J. J. EMBO J. 2003; PubMed Scopus Google Scholar). with the that AR complexes with proteins and ligand the dissociation of proteins, the and that ligand identified as and data our approach. In addition to proteins, we identified DBC1 as a protein only with liganded The DBC1 also was initially isolated in an effort to identify tumor in the human that is deleted in breast cancer. that of DBC1 is to breast cancer gene deleted in breast cancer as a breast tumor (26Hamaguchi M. Meth J.L. von Klitzing C. Wei W. Esposito D. Rodgers L. Walsh T. Welcsh P. King M.C. Wigler M.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13647-13652Crossref PubMed Scopus (189) Google Scholar). DBC1 a nuclear protein. DBC1 was shown to be during and this of DBC1 may as a mechanism to R. Chen G. Mukherjee C. White E. Oncogene. 2005; 24: 4908-4920Crossref PubMed Scopus (61) Google Scholar). We the mass data of DBC1 by using a with the mass that DBC1 was in the complexes from cells. this we and DBC1 cells and interaction by in the of The result in that more DBC1 was with in with from the cells treated with R1881. the interaction between the endogenous DBC1 and AR, we also using cell from prostate cancer cells treated with or without R1881. The result in an between DBC1 and AR. DBC1 with we DBC1 interacts or with AR. As SWI/SNF with liganded AR DBC1 with AR through its with SWI/SNF or an protein. mass the of SRC/p160 family proteins in the liganded AR we by We nuclear with members of SRC/p160 family coactivators and SWI/SNF and the of that DBC1 with or or with or of human As a was in the with and that DBC1 is with the SRC/p160 members that DBC1 is to with liganded AR. DBC1 interacts with liganded AR, we AR with either of the AR N-terminal domain or the C-terminal ligand binding domain in cells. The cell with in vitro DBC1 in the of of and was using We that was with the C-terminal ligand binding domain with AR N-terminal domain In we that DBC1 to to in in vitro and data a interaction between AR and We the AR interaction domain in of DBC1 R. Chen G. Mukherjee C. White E. Oncogene. 2005; 24: 4908-4920Crossref PubMed Scopus (61) Google Scholar) was and with and interaction with AR was using in in vitro The that of the N-terminal including the nuclear and the the whereas of the C-terminal and domains The N-terminal was only also for binding of In a in vitro AR was to containing amino to we that DBC1 interacts with AR, and this interaction AR and the N-terminal of DBC1 as an AR that DBC1 interacts with AR in a we AR transcriptional activity. We cells with an and AR in the or of the cells treated with or without and for activity. result in that addition of DBC1 enhanced AR transcriptional in a the we also the for DBC1 to enhance AR We is to with AR was to facilitate AR activation using showed that DBC1 and to a the other of the N-terminal AR interaction domain also impaired the DBC1 whereas of the C-terminal domain the activity. showed that both to that interaction with AR is required for DBC1 to facilitate AR transcriptional the role of DBC1 in AR transcriptional we to DBC1 knockdown cells using for DBC1 and We that the of cells showed a of DBC1 We transfected the cells with AR and and for AR transcriptional activity. We that knockdown of DBC1 the AR transcriptional that the of AR was by the of DBC1 An in the of AR protein was a result of AR by R1881. data that DBC1 is required for optimal transcriptional activation by AR. 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DBC1 AR DNA-binding in that DBC1 AR binding to chromatin in Xenopus and in cells to the underlying this we and DBC1 from cells We DBC1 binding of AR to a androgen using a gel shift a DNA binding by AR with addition of recombinant DBC1 drastically enhanced AR DNA-binding in a manner that DBC1 to DNA that DBC1 enhanced the of complex by AR DNA-binding activity. This was to DBC1, addition of or proteins In this we of a reversible to complexes in cells. We then isolated AR-associated proteins and by purification of AR. this proteins to from Thus, our approach is to one or more proteins that to AR, that is a with this we identified and as AR-associated proteins in the of ligand is well that proteins with AR to AR in a and that binding of hormone dissociation of proteins and of AR from (3Gelmann E.P. J. Clin. Oncol. 2002; 20: 3001-3015Crossref PubMed Scopus (769) Google Scholar, Y. P.J. 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However, is DBC1 enhanced AR transcriptional through its to facilitate AR DNA-binding activity. a number of proteins have been reported as AR coactivators R. G. W. J. PubMed Scopus Google Scholar), have been shown to enhance AR DNA-binding activity. the of this AR cofactors are and DNA-binding of hormone receptors such as and AR P. M. L. L. Mol. Cell Biol. 1998; PubMed Scopus Google Scholar, G. A. E. W. J. 2002; PubMed Scopus Google Scholar). was shown to enhance AR DNA-binding and transcriptional L. L. M. C. M. G. M. G. L. C. Oncogene. PubMed Scopus Google Scholar). Thus, an important in this was that DBC1 only enhanced AR DNA-binding in also that was required for binding of AR to the in cells. recombinant DBC1 was to enhance AR DNA-binding in gel shift the interaction between DBC1 and AR was to AR DNA-binding activity. In our DBC1 to DNA in in vitro gel shift Like and DBC1 enhanced AR DNA-binding is interaction between AR and DBC1, be DBC1 may with AR and AR a DNA DBC1 may also with DNA with AR and the to the molecular mechanism by DBC1 facilitates AR DNA-binding activity. the of this Mol. PubMed Scopus Google Scholar) reported the identification of DBC1 as an protein. DBC1 interacts with the ligand-binding domain of ERα, and this interaction is DBC1 was shown to play a critical role in the of and of human breast cancer cells. However, are in of DBC1 interaction and between and AR. DBC1 interacts with AR in a whereas interacts with in a DBC1 is a critical AR coactivator, whereas to transcriptional activity. DBC1 to the of AR. have reported of DBC1 in breast L. D. S. C. A. G. K. K. W. J. J. D. J. J. M. M. P. R. J. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar, Wang A. M. A. J.D. S. 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