Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth.
Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.
Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Urology, Nihon University School of Medicine, Tokyo, Japan.
D
D
Obinata
Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Functional Biogerontrogy, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
K
K
Takayama
Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
K
K
Fujiwara
Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
T
T
Suzuki
Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan.
S
S
Tsutsumi
Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
N
N
Fukuda
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan.
H
H
Nagase
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
T
T
Fujimura
Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
T
T
Urano
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Y
Y
Homma
Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan.
H
H
Aburatani
Department of Urology, Nihon University School of Medicine, Tokyo, Japan.
S
S
Takahashi
Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Functional Biogerontrogy, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.|Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
S
S
Inoue
D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D023281:Genomics; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009757:Nylons / Q000737:chemistry / Q000494:pharmacology*; D050811:Octamer Transcription Factor-1 / Q000235:genetics* / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D007093:Imidazoles; D009757:Nylons; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D011758:Pyrroles; D011944:Receptors, Androgen; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase