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

Nat Commun. 2021 Jun 18;12(1):3766. doi: 10.1038/s41467-021-23974-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nuclear Respiratory Factor 1 / metabolism
  • Octamer Transcription Factor-3 / genetics*
  • Octamer Transcription Factor-3 / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Receptors, Androgen / metabolism*
  • Ribavirin / pharmacology
  • Signal Transduction
  • Transcriptome / genetics


  • Antineoplastic Agents
  • Foxa1 protein, mouse
  • Hepatocyte Nuclear Factor 3-alpha
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Receptors, Androgen
  • Ribavirin