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Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth

Oncogene volume 35, pages 6350–6358 (2016)Cite this article

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Abstract

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.

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Acknowledgements

We thank N Sasaki, T Oishi, S Takada, A Ito and E Sakamoto for technical assistance. This work was supported by grants of the Cell Innovation Program (SI) and P-Direct (SI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; by Grants-in-Aid for SI (no. 15K15353), KT (no. 15K15581), TU (no. 25293214) and ST (no. 15K10610) from the Japan Society for the Promotion of Science (JSPS), Japan; by Grants-in-Aid (SI) from the MHLW, Japan; by the 2010 Research Grant of the 60th Anniversary Memorial Fund (DO) from Nihon University Medical Alumni Association; by the Young Researcher Promotion Grant (DO) from The Japanese Urological Association; by the Advanced Research for Medical Products Mining Program (SI), NIBIO, Japan; by grants from Takeda Science Foundation (SI and KT), by a grant from Mochida Memorial Research Foundation (KT), Japan.

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Author notes

  1. D Obinata and K Takayama: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    D Obinata, K Takayama, T Urano & S Inoue

  2. Department of Urology, Nihon University School of Medicine, Tokyo, Japan

    D Obinata & S Takahashi

  3. Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    K Takayama, T Urano & S Inoue

  4. Department of Functional Biogerontrogy, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    K Takayama & S Inoue

  5. Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

    K Fujiwara

  6. Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan

    T Suzuki

  7. Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan

    S Tsutsumi & H Aburatani

  8. Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

    N Fukuda

  9. Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan

    H Nagase

  10. Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    T Fujimura & Y Homma

  11. Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan

    S Inoue

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Correspondence to S Inoue.

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Obinata, D., Takayama, K., Fujiwara, K. et al. Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth. Oncogene 35, 6350–6358 (2016). https://doi.org/10.1038/onc.2016.171

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