UNC45A confers resistance to histone deacetylase inhibitors and retinoic acid.
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.
Netherlands Cancer Institute, Division of Molecular Carcinogenesis, Amsterdam, the Netherlands.
Mirjam T
MT
Epping
Lars A T
LA
Meijer
Johannes L
JL
Bos
René
R
Bernards
D000595:Amino Acid Sequence; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C509158:UNC45A protein, human; D014212:Tretinoin; D006655:Histone Deacetylases