title: NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis.
abstract: The pluripotency transcription factor NANOG has been implicated in tumor development, and NANOG-expressing cancer cells manifest stem cell properties that sustain tumor homeostasis, mediate therapy resistance and fuel tumor progression. However, how NANOG converges on somatic circuitry to trigger oncogenic reprogramming remains obscure. We previously reported that inducible NANOG expression propels the emergence of aggressive castration-resistant prostate cancer phenotypes. Here we first show that endogenous NANOG is required for the growth of castration-resistant prostate cancer xenografts. Genome-wide chromatin immunoprecipitation sequencing coupled with biochemical assays unexpectedly reveals that NANOG co-occupies a distinctive proportion of androgen receptor/Forkhead box A1 genomic loci and physically interacts with androgen receptor and Forkhead box A1. Integrative analysis of chromatin immunoprecipitation sequencing and time-resolved RNA sequencing demonstrates that NANOG dynamically alters androgen receptor/Forkhead box A1 signaling leading to both repression of androgen receptor-regulated pro-differentiation genes and induction of genes associated with cell cycle, stem cells, cell motility and castration resistance. Our studies reveal global molecular mechanisms whereby NANOG reprograms prostate cancer cells to a clinically relevant castration-resistant stem cell-like state driven by distinct NANOG-regulated gene clusters that correlate with patient survival. Thus, reprogramming factors such as NANOG may converge on and alter lineage-specific master transcription factors broadly in somatic cancers, thereby facilitating malignant disease progression and providing a novel route for therapeutic resistance.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Collene R
authors.initials: CR
authors.lastname: Jeter
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Bigang
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Hsueh-Ping
authors.initials: HP
authors.lastname: Chao
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Dingxiao
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Qiuhui
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kiera
authors.initials: K
authors.lastname: Rycaj
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Calhoun-Davis
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA; Cancer Stem Cell Institute, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China; Centers for Cancer Epigenetics, Stem Cell and Developmental Biology, RNA Interference and Non-coding RNAs and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
keywords: AR; FOXA1; NANOG; cancer stem cells; castration resistance; prostate cancer