Topoisomerase IIbeta negatively modulates retinoic acid receptor alpha function: a novel mechanism of retinoic acid resistance.
Interactions between retinoic acid (RA) receptor alpha (RARalpha) and coregulators play a key role in coordinating gene transcription and myeloid differentiation. In patients with acute promyelocytic leukemia (APL), the RARalpha gene is fused with the promyelocytic leukemia (PML) gene via the t(15;17) translocation, resulting in the expression of a PML/RARalpha fusion protein. Here, we report that topoisomerase II beta (TopoIIbeta) associates with and negatively modulates RARalpha transcriptional activity and that increased levels of and association with TopoIIbeta cause resistance to RA in APL cell lines. Knockdown of TopoIIbeta was able to overcome resistance by permitting RA-induced differentiation and increased RA gene expression. Overexpression of TopoIIbeta in clones from an RA-sensitive cell line conferred resistance by a reduction in RA-induced expression of target genes and differentiation. Chromatin immunoprecipitation assays indicated that TopoIIbeta is bound to an RA response element and that inhibition of TopoIIbeta causes hyperacetylation of histone 3 at lysine 9 and activation of transcription. Our results identify a novel mechanism of resistance in APL and provide further insight to the role of TopoIIbeta in gene regulation and differentiation.
McNamara
Suzan
S
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Segal Cancer Center, 3755 Chemin de la Côte-Ste-Catherine, Montreal, Quebec, Canada.
Wang
Hongling
H
Hanna
Nessrine
N
Miller
Wilson H
WH
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006098:Granulocytes / Q000166:cytology; D006657:Histones / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000187:drug effects*; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000187:drug effects; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006657:Histones; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C082925:retinoic acid receptor beta; D014212:Tretinoin; D004250:DNA Topoisomerases, Type II