Journal Article

ONECUT2 is a driver of neuroendocrine prostate cancer

Zhang, Yuzhe, Bristow, Robert G., van der Kwast, Theo, Boutros, Paul C., Xu, Xin, Feng, Felix Y., Zhang, Si, Poirier, John T., Hua, Junjie Tony, Puca, Loredana, Gleave, Martin, Sheahan, Anjali V., Fazli, Ladan, He, Housheng Hansen, Ellis, Leigh, Tsao, Ming-Sound, Ci, Xinpei, Lin, Dong, Liang, Yi, Ahmed, Musaddeque, Li, Estelle, Berlin, Alejandro, Haibe-Kains, Benjamin, Soares, Fraser, Zoubeidi, Amina, Guo, Haiyang, Rudin, Charles M., Wouters, Bradly G., Koritzinsky, Marianne, Xu, Jing, Beltran, Himisha, Su, Peiran, Nguyen, Tran, Xue, Hui, Vosoughi, Aram, Chen, Sujun, Mahamud, Osman, Wang, Yuzhuo, Vellanki, Ravi N., Ba-Alawi, Wail

2019

Overview

Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients. Neuroendocrine prostate cancer (NEPC) is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, resulting in resistance to AR-targeted therapy. Here they report ONECUT2 to drive NEPC tumorigenesis via regulation of hypoxia signaling and tumor hypoxia, and find hypoxia directed therapy to be effective in NEPC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 45 / 45/29 / 49 / 49/15 / 49/22 / 49/23 / 49/88 / 49/91 / 631/67/327 / 631/67/589/466 / 64/60 / Androgen receptors / Androgens / Animals / Carcinogenesis - genetics / Carcinogenesis - pathology / Cell Hypoxia - drug effects / Cell Hypoxia - genetics / Cell Line, Tumor / Cell Proliferation - drug effects / Datasets as Topic / Disease Progression / Ectopic expression / Fibers / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humanities and Social Sciences / Humans / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Light sources / Male / Mice / Mice, Inbred NOD / Mice, SCID / multidisciplinary / Neuroendocrine Tumors - genetics / Neuroendocrine Tumors - pathology / Nitroimidazoles - pharmacology / Nonlinear response / Optical fibers / Optics / Phosphoramide Mustards - pharmacology / Prostate - pathology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Signal Transduction - genetics / Smad3 Protein - genetics / Smad3 Protein - metabolism / Solitary waves / Transcription Factors - genetics / Transcription Factors - metabolism / Tumors / Up-Regulation / Xenograft Model Antitumor Assays