Abstract
The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in lambda-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration.
Highlights
Signaling pathways such as the Wnt, Hh, transforming growth factor-β, and receptor tyrosine kinases, all converge on the MYC gene family which encodes oncogenic transcription factors [1, 2]
ornithine decarboxylase (Odc) is one of the most established Myc target genes, but a previous report [11] and the Myc target gene database2 suggest that other genes encoding polyamine biosynthetic
We have focused our attention on Srm and evaluated its regulation and importance in Myc overexpressing cells
Summary
Signaling pathways such as the Wnt, Hh, transforming growth factor-β, and receptor tyrosine kinases, all converge on the MYC gene family which encodes oncogenic transcription factors [1, 2]. MYC (encoding c-Myc), MYCN (encoding N-Myc), and MYCL (encoding L-Myc) become overexpressed by direct means due to genomic translocations and amplifications in B-cell malignancies, neuroblastoma, breast cancer, and lung cancer [1]. These facts, taken together, suggest that Myc overexpression is a hallmark of cancer. Myc and its obligatory dimerization partner Max bind to CACGTG E-boxes present in a large subset of genes [3]. Max can bind the Mad/Mnt family of transrepressors and the levels (and possibly affinities) of Myc proteins or Mad/Mnt proteins decide whether a Max-containing dimer will stimulate or inactivate a gene.
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