TY - JOUR
T1 - Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer
AU - Takayama, Ken ichi
AU - Kosaka, Takeo
AU - Suzuki, Takashi
AU - Hongo, Hiroshi
AU - Oya, Mototsugu
AU - Fujimura, Tetsuya
AU - Suzuki, Yutaka
AU - Inoue, Satoshi
N1 - Funding Information:
This research was supported by grants of P-CREATE (number JP18ck0106194 from AMED, Japan (S.I.); by grants from the JSPS (number 21H04829, 20K21667 (S.I.) and number 17H04334 (K.T.)), Japan; by grants from Takeda Science Foundation, Japan (S.I. and K.T.); by grants from Sagawa Foundation for Promotion of Cancer Research (K.T.), Japan; by grants from The Mochida Memorial Foundation for Medical and Pharmaceutical Research (K.T.), Japan.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-23974-4
DO - 10.1038/s41467-021-23974-4
M3 - Article
C2 - 34145268
AN - SCOPUS:85108094090
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3766
ER -
