Novel Regulation of Nuclear Factor-YB by miR-485-3p Affects the Expression of DNA Topoisomerase IIα and Drug Responsiveness
- 20 January 2011
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 79 (4), 735-741
- https://doi.org/10.1124/mol.110.069633
Abstract
Nuclear factor (NF)-YB, a subunit of the transcription factor nuclear factor Y (NF-Y) complex, binds and activates CCAAT-containing promoters. Our previous work suggested that NF-YB may be a mediator of topoisomerase IIα (Top2α), working through the Top2α promoter. DNA topoisomerase II (Top2) is an essential nuclear enzyme and the primary target for several clinically important anticancer drugs. Our teniposide-resistant human lymphoblastic leukemia CEM cells (CEM/VM-1-5) express reduced Top2α protein compared with parental CEM cells. To study the regulation of Top2α during the development of drug resistance, we found that NF-YB protein expression is increased in CEM/VM-1-5 cells compared with parental CEM cells. This further suggests that increased NF-YB may be a negative regulator of Top2α in CEM/VM-1-5 cells. We asked what causes the up-regulation of NF-YB in CEM/VM-1-5 cells. We found by microRNA profiling that hsa-miR-485-3p is lower in CEM/VM-1-5 cells compared with CEM cells. MicroRNA target prediction programs revealed that the 3′-untranslated region (3′-UTR) of NF-YB harbors a putative hsa-miR-485-3p binding site. We thus hypothesized that hsa-miR-485-3p mediates drug responsiveness by decreasing NF-YB expression, which in turn negatively regulates Top2α expression. To test this, we overexpressed miR-485-3p in CEM/VM-1-5 cells and found that this led to reduced expression of NF-YB, a corresponding up-regulation of Top2α, and increased sensitivity to the Top2 inhibitors. Results in CEM cells were replicated in drug-sensitive and -resistant human rhabdomyosarcoma Rh30 cells, suggesting that our findings represent a general phenomenon. Ours is the first study to show that miR-485-3p mediates Top2α down-regulation in part by altered regulation of NF-YB.Keywords
This publication has 36 references indexed in Scilit:
- DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial DrugsCell Chemical Biology, 2010
- Hyaluronan-CD44 Interaction with Protein Kinase Cϵ Promotes Oncogenic Signaling by the Stem Cell Marker Nanog and the Production of MicroRNA-21, Leading to Down-regulation of the Tumor Suppressor Protein PDCD4, Anti-apoptosis, and Chemotherapy Resistance in Breast Tumor CellsPublished by Elsevier BV ,2009
- DNA topoisomerase II and its growing repertoire of biological functionsNature Reviews Cancer, 2009
- Targeting DNA topoisomerase II in cancer chemotherapyNature Reviews Cancer, 2009
- Suppression of cell growth and invasion by miR-205 in breast cancerCell Research, 2009
- A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 functionNature Genetics, 2009
- CellMiner: a relational database and query tool for the NCI-60 cancer cell linesBMC Genomics, 2009
- Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancerOncogene, 2008
- Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytesOncogene, 2007
- Cellular roles of DNA topoisomerases: a molecular perspectiveNature Reviews Molecular Cell Biology, 2002