Abstract 4479: Cancer cell ribogenesis: MYC and the integrity of the RNA polymerase I-rRNA machinery

Abstract

Abstract Upregulation of RNA Polymerase (Pol I)-mediated transcription of ribosomal RNA (rRNA) and increased ribogenesis, which are necessary to sustain the increased metabolic demand of highly proliferating cancer cells, are hallmarks of cancer. Increased rRNA transcription can be due deregulation of tumor suppressors and oncogenes that affect Pol I activity. Overexpression of the MYC oncogene, a potent Pol I activators, is particularly frequent in cancer. In addition, based on our analysis of the Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is also frequent in cancers of various histotype (Rossetti et al., Cell Cycle, 2016). By using breast and ovarian epithelial cells, we mechanistically found that: 1) ectopic expression of either MYC or RRN3 (TIF-IA), a key Pol I basal component, by increasing rRNA synthesis, is sufficient to induce in vitro transformation phenotypes and to promote cell proliferation; 2) there is a causal link between MYC overexpression and RRN3 upregulation; 3) MYC- or RRN3-induced rRNA upregulation sensitizes cells to the anti-proliferative action of drugs inhibiting rRNA transcription. Our findings provide a rationale for using drugs targeting rRNA transcription to curb proliferation of cancers cells due to rRNA upregulation by MYC. Funding for this study was provided by an RPCI-UPCI Ovarian Cancer Spore DRP award (NS), the NCI R01 CA127614 grant (NS), the Terri Brodeur Breast Cancer Foundation (SR), the Susan Komen Foundation (SR), and the NCI P30 CA016056 institutional grant. Citation Format: Stefano Rossetti, Andrzej J. Wierzbicki, Nicoletta Sacchi. Cancer cell ribogenesis: MYC and the integrity of the RNA polymerase I-rRNA machinery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4479. doi:10.1158/1538-7445.AM2017-4479