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

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.

OCT1-target neural gene PFN2 promotes tumor growth in androgen receptor-negative prostate cancer

“…On the other hand, OCT1 is widely expressed, including in the placenta, rectum and testis (Human Protein Atlas available from http://www.proteinatlas.org ), in the human body among the eight OCT proteins, and known to be associated with the master regulator of pluripotency, octamer-binding transcription factor 4 (OCT4), in stem cells 28 – 30 . We recently reported that OCT4 associates with Nuclear Respiratory Factor 1 (NRF1) in AR-negative PC and consists an important component of the TF complex in CRPC 31 . Interestingly, OCT1 binding sites were enriched in a series of genes that are regulated by MYC in MYC-driven lung adenocarcinomas 32 , suggesting that OCT1 and MYC may co-regulate a series of androgen-responsive genes in PC.…”

“…LNCaP, 22RV1, PC3 are cultured using RPMI-1640 and DU145 using DMEM medium, respectively, and both are supplemented with 10% FBS, 50 U/mL penicillin and 50 μg/mL streptomycin, in addition, some of LNCaP and 22Rv1 cells are treated with 100 nM of dihydrotestosterone (DHT) (Wako, Tokyo, Japan) for 3 days 14 . Short tandem repeat (STR) analysis was performed to authenticate the cell lines used in the present study 31 , 42 . Also, these cells have been checked for Mycoplasma contamination using real-time PCR performed by Funakoshi Co., Ltd. (Tokyo, Japan).…”

The emerging potentials of lncRNA DRAIC in human cancers

“…The androgen receptor (AR) plays a crucial role in the pathogenesis of PCa and is considered a clinically validated target for the treatment of PCa ( 41 – 44 ). Unfortunately, long-term androgen deprivation can ultimately lead to castration-resistant PCa (CRPC), which favors metastasis and poor prognosis ( 45 – 47 ). Although much effort has been made to improve PCa treatment, it is still needed to identify more sensitive biomarkers to guide early diagnosis and treatment ( 37 , 48 , 49 ).…”

Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1

“…Among them, Nrf1 is identified as an evolutionarily conserved transcription activator that binds to GC-rich DNA elements in promoters of a host of nuclear genes encoding proteins involved in mitochondrial structure and functions [ 11 , 12 , 13 , 14 , 15 ]. Multiple studies using ChIP-seq analysis have identified distinct sets of Nrf1’s target genes in different cell types, suggesting that Nrf1 acts in a context-dependent manner in regulating cell growth, differentiation, and mitochondrial biogenesis [ 16 , 17 , 18 , 19 ]. In addition, Nrf1 interacts with other proteins involved in different cellular functions.…”