ONECUT2 is a Targetable Master Regulator of Lethal Prostate Cancer that Suppresses the Androgen Axis

Autor: Michael R. Freeman, Dolores Di Vizio, Kenneth Steadman, Alberto Yáñez, Eva Corey, Colm Morrissey, Wen-Chin Huang, Stephen J. Freedland, Simon G. Coetzee, Dennis J. Hazelett, Fangjin Huang, Mariana Reis-Sobreiro, Ramachandran Murali, Sungyong You, Peter S. Nelson, Beatrice S. Knudsen, Chia-Yi Chu, Leland W.K. Chung, Xinlei Pan, Julie Yang, Isla P. Garraway, Mirja Rotinen
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Drug Resistance
Castration-Resistant
Androgen suppression
Medical and Health Sciences
Androgen
Metastasis
Mice
Prostate cancer
Receptors
Medicine
Cancer
Tumor
Prostate Cancer
General Medicine
Gene Expression Regulation
Neoplastic
Neuroendocrine Tumors
Prostatic Neoplasms
Castration-Resistant
Receptors
Androgen
Androgens
Disease Progression
Adenocarcinoma
Biotechnology
Signal Transduction
Urologic Diseases
Hepatocyte Nuclear Factor 3-alpha
medicine.drug_class
Immunology
Antineoplastic Agents
General Biochemistry
Genetics and Molecular Biology
Article
Cell Line
03 medical and health sciences
Cell Line
Tumor
Genetics
Animals
Humans
Transcription factor
Homeodomain Proteins
Neoplastic
business.industry
Prostatic Neoplasms
medicine.disease
Xenograft Model Antitumor Assays
Androgen receptor
030104 developmental biology
Gene Expression Regulation
Drug Resistance
Neoplasm
Cancer research
Neoplasm
FOXA1
business
Transcription Factors
Zdroj: Nature medicine, vol 24, iss 12
Popis: Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor- (AR-) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.
Databáze: OpenAIRE
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