Abstract
Recent studies indicate the importance of the ubiquitin ligase Siah2 in control of more aggressive prostate tumors – namely, neuroendocrine (NE) prostate tumors and prostate adenocarcinoma (PCa) harboring neuroendocrine lesions. Siah2-dependent expression and activity of HIF-1α regulate its availability to form a transcriptional complex with FoxA2, resulting in expression of specific target genes, including Hes6, Sox9 and Jmjd1a, whose co-expression is sufficient for formation of NE tumors and NE lesions in PCa. These studies provide novel markers to diagnose and monitor formation of NE lesions and NE tumors. Furthermore, defining the regulatory axis consisting of Siah2 and HIF-1α/FoxA2 cooperation suggests novel therapeutic modalities to treat these most aggressive forms of prostate cancer. Here we review current understanding of Siah role in control of hypoxia and prostate tumor development and highlight potential approaches for targeting components along Siah-regulated pathways.
Publication types
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Research Support, N.I.H., Extramural
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Review
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / enzymology*
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Animals
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Antineoplastic Agents / pharmacology
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Biomarkers, Tumor / metabolism*
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Drug Design
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Gene Expression Regulation, Neoplastic
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Hepatocyte Nuclear Factor 3-beta / metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Male
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Molecular Targeted Therapy
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Neuroendocrine Tumors / drug therapy
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Neuroendocrine Tumors / enzymology*
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Neuroendocrine Tumors / genetics
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Neuroendocrine Tumors / pathology
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Nuclear Proteins / metabolism*
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / enzymology*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology
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Signal Transduction* / drug effects
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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FOXA2 protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Hepatocyte Nuclear Factor 3-beta
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Ubiquitin-Protein Ligases
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seven in absentia proteins