Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer

Ken-ichi Takayama, Takeo Kosaka, Takashi Suzuki, Hiroshi Hongo, Mototsugu Oya, Tetsuya Fujimura, Yutaka Suzuki and Satoshi Inoue ()
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Ken-ichi Takayama: Tokyo Metropolitan Institute of Gerontology
Takeo Kosaka: Keio University School of Medicine
Takashi Suzuki: Tohoku University Graduate School of Medicine
Hiroshi Hongo: Keio University School of Medicine
Mototsugu Oya: Keio University School of Medicine
Tetsuya Fujimura: Jichi Medical University
Yutaka Suzuki: Graduate School of Frontier Sciences, The University of Tokyo
Satoshi Inoue: Tokyo Metropolitan Institute of Gerontology

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Interactive networks of transcription factors (TFs) have critical roles in epigenetic and gene regulation for cancer progression. It is required to clarify underlying mechanisms for transcriptional activation through concerted efforts of TFs. Here, we show the essential role of disease phase-specific TF collaboration changes in advanced prostate cancer (PC). Investigation of the transcriptome in castration-resistant PC (CRPC) revealed OCT4 as a key TF in the disease pathology. OCT4 confers epigenetic changes by promoting complex formation with FOXA1 and androgen receptor (AR), the central signals for the progression to CRPC. Meanwhile, OCT4 facilitates a distinctive complex formation with nuclear respiratory factor 1 (NRF1) to gain chemo-resistance in the absence of AR. Mechanistically, we reveal that OCT4 increases large droplet formations with AR/FOXA1 as well as NRF1 in vitro. Disruption of TF collaborations using a nucleoside analogue, ribavirin, inhibited treatment-resistant PC tumor growth. Thus, our findings highlight the formation of TF collaborations as a potent therapeutic target in advanced cancer.

Date: 2021
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DOI: 10.1038/s41467-021-23974-4

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