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Research Articles: Therapeutics, Targets, and Development

Combined IFN- and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells

¹ Department of Plant Biology and Forest Genetics, Uppsala Genetic Center, Swedish University of Agricultural Sciences and ² Department of Genetics and Pathology, University of Uppsala, University Hospital, Uppsala, Sweden; ³ Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden; ⁴ Department of Laboratory Medicine, Lund University, University Hospital MAS, Malmö, Sweden; and ⁵ Institute of Cytology, Russian Academy of Science, St. Petersburg, Russia

Requests for reprints: Lars-Gunnar Larsson, Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Box 280, SE-171 77 Stockholm, Sweden. Phone: 46-8-52487239; Fax: 46-8-8330498. E-mail: Lars-Gunnar.Larsson{at}ki.se

Abstract

The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN- synergistically potentiates retinoic acid (RA)–induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastoma cells with RA+IFN- down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heterodimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Mad1/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA+IFN- treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN- and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma. [Mol Cancer Ther 2007;6(10):2634–41]

Grant support: Childhood Cancer Foundation of Sweden, Lovisa and Thielman Foundation, and Swedish Cancer Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: C. Cetinkaya and A. Hultquist contributed equally to this work.

Present address for C. Cetinkaya: Laboratory for Stem Cell Research, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark. Present address for A. Hultquist: Hematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund, Sweden.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁷ Bahram et al. (in preparation).

Received 8/14/06; revised 7/26/07; accepted 9/ 4/07.