Identification of an oncogenic network with prognostic and therapeutic value in prostate cancer

Autor:	Gennaro D'Urso, Valeria A. Copello, Ning Zhao, Laine Heidman, Kerry L. Burnstein, David J. Wiley, Stephanie Peacock, Fiorella Magani, Eric R. Bray, Maria J. Martinez
Rok vydání:	2018
Předmět:	0301 basic medicine Male Carcinogenesis RNA Splicing androgen receptor splice variants castration resistance General Biochemistry Genetics and Molecular Biology Disease-Free Survival Article Transcriptome Network Biology 03 medical and health sciences Prostate cancer Cell Line Tumor Schizosaccharomyces medicine Humans Gene Cell Proliferation Cancer mitotic gene signature General Immunology and Microbiology biology Mechanism (biology) Applied Mathematics Gene Expression Profiling Prostatic Neoplasms Articles biology.organism_classification medicine.disease Synthetic genetic array Prognosis 3. Good health Androgen receptor Gene Expression Regulation Neoplastic 030104 developmental biology Computational Theory and Mathematics yeast synthetic genetic array Drug Resistance Neoplasm Receptors Androgen Schizosaccharomyces pombe Genome-Scale & Integrative Biology Cancer research General Agricultural and Biological Sciences Information Systems Signal Transduction weighted gene co‐expression network analysis
Zdroj:	Molecular Systems Biology
ISSN:	1744-4292
Popis:	Identifying critical pathways governing disease progression is essential for accurate prognosis and effective therapy. We developed a broadly applicable and novel systems‐level gene discovery strategy. This approach focused on constitutively active androgen receptor (AR) splice variant‐driven pathways as representative of an intractable mechanism of prostate cancer (PC) therapeutic resistance. We performed a meta‐analysis of human prostate samples using weighted gene co‐expression network analysis combined with experimental AR variant transcriptome analyses. An AR variant‐driven gene module that is upregulated during human PC progression was identified. We filtered this module by identifying genes that functionally interacted with AR variants using a high‐throughput synthetic genetic array screen in Schizosaccharomyces pombe. This strategy identified seven AR variant‐regulated genes that also enhance AR activity and drive cancer progression. Expression of the seven genes predicted poor disease‐free survival in large independent PC patient cohorts. Pharmacologic inhibition of interacting members of the gene set potently and synergistically decreased PC cell proliferation. This unbiased and novel gene discovery strategy identified a clinically relevant, oncogenic, interacting gene hub with strong prognostic and therapeutic potential in PC.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::624e72dfa9f67b67e3c60840448e081e https://pubmed.ncbi.nlm.nih.gov/30108134 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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