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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1
Collene R Jeter1, Bigang Liu1, Yue Lu1
1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
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.
Insights
The transcription factor NANOG reprograms prostate cancer cells, driving castration resistance and tumor progression by altering key signaling pathways. This discovery offers insights into cancer stem cell-like states and potential therapeutic resistance mechanisms.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Stem Cell Biology
Background:
- NANOG, a pluripotency transcription factor, is linked to cancer development and stem cell properties.
- NANOG-expressing cancer cells exhibit therapy resistance and drive tumor progression.
- Prostate cancer progression to castration resistance involves complex molecular reprogramming.
Purpose of the Study:
- To elucidate the molecular mechanisms by which NANOG drives oncogenic reprogramming in prostate cancer.
- To investigate the role of endogenous NANOG in castration-resistant prostate cancer (CRPC) growth.
- To identify NANOG-regulated gene networks contributing to CRPC phenotypes.
Main Methods:
- Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) to identify NANOG binding sites.
- Biochemical assays to assess physical interactions between NANOG, androgen receptor (AR), and Forkhead box A1 (FOXA1).
- Time-resolved RNA sequencing to analyze dynamic gene expression changes.
- Analysis of CRPC xenografts and patient data.
Main Results:
- Endogenous NANOG is essential for CRPC xenograft growth.
- NANOG co-occupies AR/FOXA1 genomic loci and interacts with AR and FOXA1.
- NANOG dynamically modulates AR/FOXA1 signaling, repressing differentiation genes and inducing stem cell, motility, and castration resistance genes.
- Distinct NANOG-regulated gene clusters correlate with patient survival.
Conclusions:
- NANOG reprograms prostate cancer cells into a castration-resistant, stem cell-like state via global alterations in AR/FOXA1 signaling.
- NANOG-driven reprogramming involves specific gene clusters associated with poor patient survival.
- Reprogramming factors like NANOG may broadly impact lineage-specific transcription factors in cancer, promoting progression and therapeutic resistance.
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