ArticleCancer cell2017
Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance.
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57citing papers in PubMed
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57 citing papers in PubMed.
- Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer.Cell reports. Medicine · 2025Trial
- Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer.Nature communications · 2026Article
- Therapeutic targeting of the eIF4E cap-binding domain reveals control of lineage fate in prostate cancer.The Journal of clinical investigation · 2026Article
- Integrative Proteogenomic Characterization of Left-Sided and Right-Sided Colorectal Cancer.MedComm · 2026Article
- Missense and Intronic Variants inInternational journal of medical sciences · 2026Article
- Transcription factor switching drives subtype-specific pancreatic cancer.Nature genetics · 2025Article
- Targeting FGFR4 abrogates HNF1A-driven metastasis in pancreatic ductal adenocarcinoma.Molecular cancer · 2025Article
- Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.Nature genetics · 2025Article
- Castrate-resistant prostate cancer response to taxane is determined by an HNF1-dependent apoptosis resistance circuit.Cell reports. Medicine · 2024Article
- LBFextract: Unveiling transcription factor dynamics from liquid biopsy data.Computational and structural biotechnology journal · 2024Article
- Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen-targeted therapies.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A prostate cancer gastrointestinal transcriptional phenotype may be associated with diminished response to AR-targeted therapy.bioRxiv : the preprint server for biology · 2024Article
- Review
- Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.bioRxiv : the preprint server for biology · 2024Article
- An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.iScience · 2024Article
- Deregulated kinase action in prostate cancer: molecular basis and therapeutic implications.Endocrine-related cancer · 2023Review
- HNF4G stimulates the development of pancreatic cancer by promoting IGF2BP2 transcription.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Article
- HNF4G accelerates glioma progression by facilitating NRP1 transcription.Oncology letters · 2023Article
- Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes.Cancer discovery · 2023Article
- Intrinsic Molecular Subtypes of Metastatic Castration-Resistant Prostate Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
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Authors and funding
25 authors.
Shipra ShuklaHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Joanna CyrtaDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA.
Devan A MurphyHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Edward G WalczakHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Leili RanHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Praveen AgrawalDepartment of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Yuanyuan XieHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Yuedan ChenHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Shangqian WangHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Yu ZhanHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Dan LiYale School of Medicine, New Haven, CT 06511, USA.
Elissa W P WongHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Andrea SbonerDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Medical College, New York, NY 10065, USA.
Himisha BeltranEnglander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
Juan Miguel MosqueraDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA.
Jessica SherHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Zhen CaoHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
John WongvipatHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Richard P KocheCenter of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Anuradha GopalanDepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Deyou ZhengDepartments of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mark A RubinDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA.
Howard I ScherDepartment of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Ping ChiHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chip@mskcc.org.
Yu ChenHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: cheny1@mskcc.org.
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MSPORE In Prostate CancerP50CA092629 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI JAMES A EASTHAM · 2001 to 2026
$63.0MSPORE in Soft Tissue SarcomaP50CA140146 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI LADANYI, MARC · 2010 to 2014
$11.1MThe MSKCC-UW/Fred Hutch Prostate Cancer Drug Resistance and Sensitivity CenterU54CA224079 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI SAWYERS, CHARLES L. · 2017 to 2021
$6.8MEpitomic Biomarkers of Prostate CancerU01CA111275 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHINNAIYAN, ARUL M, RUBIN, MARK A. · 2004 to 2015
$6.8MRole of ETS factors in specifying prostate luminal cell identity and androgen receptor dependenceR01CA193837 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI SAWYERS, CHARLES L. · 2015 to 2025
$4.7MAn integrative approach to target lineage-specific oncogenic transcription factorDP2CA174499 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHI, PING · 2012 to 2012
$2.6MUnderstanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistanceR01CA208100 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHEN, YU · 2017 to 2021
$2.5MElucidating the roles of ETV1 in the pathogenesis of GISTK08CA151660 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHI, PING · 2011 to 2015
$848kUnderstanding the roles of TMPRSS2 and ERG in pathogenesis of prostate cancer.K08CA140946 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHEN, YU · 2009 to 2013
$796kNCI NIH HHS DP2 CA174499NCI NIH HHS K08 CA140946NCI NIH HHS K08 CA151660NCI NIH HHS P30 CA008748NCI NIH HHS P50 CA092629NCI NIH HHS P50 CA140146NCI NIH HHS R01 CA193837NCI NIH HHS R01 CA208100NCI NIH HHS U01 CA111275NCI NIH HHS U54 CA224079
Abstract
Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance.
Indexed as
AnimalsDrug Resistance, NeoplasmGene Expression Regulation, NeoplasticHepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 4HeterograftsHumansMaleMiceMice, SCIDProstatic Neoplasms, Castration-ResistantTrypsin Inhibitor, Kazal PancreaticHepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 4HNF1A protein, humanHNF4G protein, humanSPINK1 protein, humanTrypsin Inhibitor, Kazal Pancreaticandrogen-deprivation therapycastration resistanceChIP-seqenzalutamideHNF1AHNF4Gpioneer factorprostate cancerSPINK1
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