Targeting the BAF57 SWI/SNF subunit in prostate cancer: a novel platform to control androgen receptor activity.
The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligand-binding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics. Thus, new means must be developed to target AR activity. The SWI/SNF chromatin remodeling complex is critical for AR transcriptional activity, and the BAF57 SWI/SNF subunit facilitates direct interaction with the receptor. Although selected SWI/SNF subunit expression is reduced in prostate cancer, we show that BAF57 is retained in human disease and is elevated in a subset of tumors. Functional analyses showed that BAF57 contributes uniquely to androgen-mediated stimulation of transcription without compromising the effectiveness of AR antagonists. Subsequent studies revealed that BAF57 is recruited to the AR DNA-binding domain/hinge region, which occurs concomitant with receptor activation. These data provided the basis for a novel inhibitor derived from BAF57 [BAF57 inhibitory peptide (BIPep)], which blocked AR residence on chromatin and resultant AR-dependent gene activation. Importantly, BIPep expression was sufficient to inhibit androgen-dependent prostate cancer cell proliferation in AR-positive cells. In summary, these data identify blockade of AR-BAF57 interaction as a novel means to target agonist-induced AR function in prostate cancer, and provide the first evidence that abrogation of SWI/SNF function can be developed as a point of therapeutic intervention in prostate cancer.
Departments of Cancer Biology and Urology, and Kimmel Cancer Center, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania, USa.
Kevin A
KA
Link
Sucharitha
S
Balasubramaniam
Ankur
A
Sharma
Clay E S
CE
Comstock
Sonia
S
Godoy-Tundidor
Nathan
N
Powers
Khanh H
KH
Cao
Annemie
A
Haelens
Frank
F
Claessens
Monica P
MP
Revelo
Karen E
KE
Knudsen
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059002:Androgen Receptor Antagonists; D000818:Animals; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008297:Male; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D021122:Protein Subunits; D012333:RNA, Messenger; D011944:Receptors, Androgen; C504738:SMARCE1 protein, human