| UNC45A confers resistance to histone deacetylase inhibitors and retinoic acid. | |
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MedLine Citation:
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PMID: 19843631 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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To identify potential biomarkers of therapy response, we have previously done a large-scale gain-of-function genetic screen to identify genes whose expression confers resistance to histone deacetylase inhibitors (HDACI). This genetic screen identified two genes with a role in retinoic acid signaling, suggesting that HDACIs target retinoic acid signaling as part of their anticancer effect. We study here a third gene identified in this genetic screen, UNC45A, and assess its role in retinoic acid signaling and responses to HDACIs using cell-based proliferation and differentiation assays and transcriptional reporter gene assays. The vertebrate Unc45 genes are known for their roles in muscle development and the assembly and cochaperoning of the muscle motor protein myosin. Here, we report that human UNC45A (GCUNC45) can render transformed cells resistant to treatment with HDACIs. We show that UNC45A also inhibits signaling through the retinoic acid receptor alpha. Expression of UNC45A inhibits retinoic acid-induced proliferation arrest and differentiation of human neuroblastoma cells and inhibits the induction of endogenous retinoic acid receptor target genes. These data establish an unexpected role for UNC45A in causing resistance to both HDACI drugs and retinoic acid. Moreover, our data lend further support to the notion that HDACIs exert their anticancer effect, at least in part, through an effect on retinoic acid signaling. |
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Authors:
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Mirjam T Epping; Lars A T Meijer; Johannes L Bos; René Bernards |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-10-20 |
Journal Detail:
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Title: Molecular cancer research : MCR Volume: 7 ISSN: 1557-3125 ISO Abbreviation: Mol. Cancer Res. Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101150042 Medline TA: Mol Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1861-70 Citation Subset: IM |
Affiliation:
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Netherlands Cancer Institute, Division of Molecular Carcinogenesis, Amsterdam, the Netherlands. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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