Loss of NCOA6 protein causes aggressive prostate cancer with EGFR overexpression and dependency.
8 affiliations
- 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
- 2Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
- 3Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- 4Dan L. Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.
- 5Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
- 6Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
- 7Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Lombardy, Italy.
- 8Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
Abstract
Loss of tumor suppressors can drive carcinogenesis while simultaneously creating actionable therapeutic vulnerabilities. Epidermal growth factor receptor (EGFR) is frequently overexpressed in prostate cancer (PCa), yet EGFR inhibitors have shown limited clinical benefit, and the basis for this variability remains unclear. Here, analysis of 1,719 human PCa specimens reveals frequent downregulation of the nuclear receptor coactivator 6 (NCOA6), particularly in metastatic disease. Genetic loss of NCOA6 accelerates tumor growth in human PCa xenografts, induces prostate tumorigenesis in mice, and cooperates with Pten haploinsufficiency to drive aggressive metastatic PCa. Mechanistically, NCOA6 forms a repressive complex with nuclear transcription factor Y (NFY) at a distal EGFR enhancer, blocking p300 recruitment and limiting EGFR transcription. Loss of NCOA6 derepresses EGFR, causing EGFR overexpression and rendering both androgen-sensitive and castration-resistant PCa highly dependent on EGFR signaling and exquisitely sensitive to EGFR inhibition. These findings identify NCOA6 as a potent tumor suppressor and a clinically relevant biomarker to stratify PCa patients most likely to benefit from EGFR-targeted therapy.
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BibTeX
@article{liu2026loss,
title = {{Loss of NCOA6 protein causes aggressive prostate cancer with EGFR overexpression and dependency.}},
author = {Yonghong Liu and Zhangwei Tong and Qianxing Mo and Xiaohui Peng and Antrix Jain and Sung Yun Jung and Patricia Castro and Mu Yang and Lan Liao and Roberto Mantovani and Fen Wang and Michael M Ittmann and Jianming Xu},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77701-y},
url = {https://europepmc.org/article/MED/42875450},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Loss of NCOA6 protein causes aggressive prostate cancer with EGFR overexpression and dependency.
AU - Yonghong Liu
AU - Zhangwei Tong
AU - Qianxing Mo
AU - Xiaohui Peng
AU - Antrix Jain
AU - Sung Yun Jung
AU - Patricia Castro
AU - Mu Yang
AU - Lan Liao
AU - Roberto Mantovani
AU - Fen Wang
AU - Michael M Ittmann
AU - Jianming Xu
PY - 2026
DA - 2026/09/15
JO - Nature communications
DO - 10.1038/s41467-026-77701-y
UR - https://europepmc.org/article/MED/42875450
AB - Loss of tumor suppressors can drive carcinogenesis while simultaneously creating actionable therapeutic vulnerabilities. Epidermal growth factor receptor (EGFR) is frequently overexpressed in prostate cancer (PCa), yet EGFR inhibitors have shown limited clinical benefit, and the basis for this variability remains unclear. Here, analysis of 1,719 human PCa specimens reveals frequent downregulation of the nuclear receptor coactivator 6 (NCOA6), particularly in metastatic disease. Genetic loss of NCOA6 accelerates tumor growth in human PCa xenografts, induces prostate tumorigenesis in mice, and cooperates with Pten haploinsufficiency to drive aggressive metastatic PCa. Mechanistically, NCOA6 forms a repressive complex with nuclear transcription factor Y (NFY) at a distal EGFR enhancer, blocking p300 recruitment and limiting EGFR transcription. Loss of NCOA6 derepresses EGFR, causing EGFR overexpression and rendering both androgen-sensitive and castration-resistant PCa highly dependent on EGFR signaling and exquisitely sensitive to EGFR inhibition. These findings identify NCOA6 as a potent tumor suppressor and a clinically relevant biomarker to stratify PCa patients most likely to benefit from EGFR-targeted therapy.
SN - 2041-1723
ER -