Abstract
The oncogenic transcription factor Myc is required for the progression and maintenance of diverse tumors. This has led to the concept that Myc itself, Myc-activated gene products, or associated biological processes might constitute prime targets for cancer therapy. Here, we present an in vivo reverse-genetic screen targeting a set of 241 Myc-activated mRNAs in mouse B-cell lymphomas, unraveling a critical role for the mitochondrial ribosomal protein (MRP) Ptcd3 in tumor maintenance. Other MRP-coding genes were also up regulated in Myc-induced lymphoma, pointing to a coordinate activation of the mitochondrial translation machinery. Inhibition of mitochondrial translation with the antibiotic Tigecycline was synthetic-lethal with Myc activation, impaired respiratory activity and tumor cell survival in vitro, and significantly extended lifespan in lymphoma-bearing mice. We have thus identified a novel Myc-induced metabolic dependency that can be targeted by common antibiotics, opening new therapeutic perspectives in Myc-overexpressing tumors.
Highlights
Tumors driven by deregulated c-myc generally show oncogene addiction, being sensitive to suppression or inhibition of the c-Myc protein [1, 2]
Analogous to a previous study [10], we constructed a retroviral shRNA library targeting a subset of 241 Myc-induced genes, each mRNA being targeted with 5 different shRNAs (Supplementary Table S1)
To ensure high-stringency selection criteria, we followed-up only on genes targeted by two or more depleted shRNAs, with at least one shRNA depleted > 5 fold in all four replicates. 41 genes were selected for further validation in a secondary in vitro competition screen (Figure 1A; Supplementary Table S3), in which we individually tested 2-4 shRNAs per gene: from a total of 105 shRNAs, 78 (74%) conferred competitive disadvantage of infected (GFP+) relative to non-infected (GFP-) lymphoma cells, validating their initial dropout in vivo (Supplementary Table S4; Figure 1C). 27 genes were validated in this manner, with at least two independent shRNAs conferring negative selection in the secondary screen (Supplementary Table S5)
Summary
Tumors driven by deregulated c-myc generally show oncogene addiction, being sensitive to suppression or inhibition of the c-Myc protein (hereby, Myc) [1, 2]. Myc is a bHLH-LZ family transcription factor that requires dimerization with the partner protein Max in order to bind DNA and regulate gene expression [5]. When over-expressed, Myc activates and represses large sets of target genes, among which must lie the critical effectors of its oncogenic activity [6,7,8,9]. RNAi-based screens have been employed to identify genes that show synthetic lethality with Myc activation or are required for the progression of Myc-driven tumors [1014]. Only a handful of established Myc-target genes were involved so far [12, 15,16,17,18,19]. No screen systematically addressed the functional requirement of Myc-regulated genes in a given tumor type
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