Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers.

Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine Houston Texas

Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer Center Houston Texas

Department of Molecular and Cellular Biology Baylor College of Medicine Houston Texas

Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Medical Scientist Training Program Baylor College of Medicine Houston Texas

The School of Chemistry and Molecular Biosciences The University of Queensland Brisbane Australia

Therapeutic Innovation Center Baylor College of Medicine Houston Texas

Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology Baylor College of Medicine Houston Texas

Zobrazit více v PubMed

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. PubMed

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. PubMed

Lien EC, Lyssiotis CA, Cantley LC. Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. Recent Results Cancer Res 2016;207:39–72. PubMed

Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. . Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010;39:171–83. PubMed PMC

Sullivan LB, Gui DY, Van Der Heiden MG. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Cancer 2016;16:680–93. PubMed

Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, et al. . Functional genomic landscape of human breast cancer drivers, vulnerabilities, and resistance. Cell 2016;164:293–309. PubMed PMC

Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009;136:823–37. PubMed PMC

Dang CV. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med 2013;3:a014217. PubMed PMC

Herold S, Herkert B, Eilers M. Facilitating replication under stress: an oncogenic function of MYC? Nat Rev Cancer 2009;9:441–4. PubMed

Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, et al. . A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 2012;335:348–53. PubMed PMC

Liu L, Ulbrich J, Müller J, Wüstefeld T, Aeberhard L, Kress TR, et al. . Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 2012;483:608–12. PubMed

David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2010;463:364–8. PubMed PMC

Guccione E, Martinato F, Finocchiaro G, Luzi L, Tizzoni L, Dall’ Olio V, et al. . Myc-binding-site recognition in the human genome is determined by chromatin context. Nat Cell Biol 2006;8:764–70. PubMed

Herkert B, Eilers M. Transcriptional repression: the dark side of myc. Genes Cancer 2010;1:580–6. PubMed PMC

Wiese KE, Walz S, von Eyss B, Wolf E, Athineos D, Sansom O, et al. . The role of MIZ-1 in MYC-dependent tumorigenesis. Cold Spring Harb Perspect Med 2013;3:a014290. PubMed PMC

Muhar M, Ebert A, Neumann T, Umkehrer C, Jude J, Wieshofer C, et al. . SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis. Science 2018;360:800–5. PubMed PMC

Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, et al. . Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature 2014;511:483–7. PubMed PMC

Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev 2008;22:2755–66. PubMed PMC

Sabò A, Amati B. Genome recognition by MYC. Cold Spring Harb Perspect Med 2014;4:a014191. PubMed PMC

Iritani BM, Eisenman RN. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc Natl Acad Sci U S A 1999;96:13180–5. PubMed PMC

Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN, et al. . c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol 2005;7:311–8. PubMed

Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E, et al. . Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 2008;456:971–5. PubMed PMC

Cunningham JT, Moreno MV, Lodi A, Ronen SM, Ruggero D. Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 2014;157:1088–103. PubMed PMC

Mannava S, Grachtchouk V, Wheeler LJ, Im M, Zhuang D, Slavina EG, et al. . Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells. Cell Cycle 2008;7:2392–400. PubMed PMC

Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, et al. . c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 2012;151:68–79. PubMed PMC

Lin CY, Lovén J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. . Transcriptional amplification in tumor cells with elevated c-Myc. Cell 2012;151:56–67. PubMed PMC

Patange S, Ball DA, Wan Y, Karpova TS, Girvan M, Levens D, et al. . MYC amplifies gene expression through global changes in transcription factor dynamics. Cell Rep 2022;38:110292. PubMed PMC

Ruggero D. The role of Myc-induced protein synthesis in cancer. Cancer Res 2009;69:8839–43. PubMed PMC

Ruggero D, Pandolfi PP. Does the ribosome translate cancer? Nat Rev Cancer 2003;3:179–92. PubMed

Liu Y-C, Li F, Handler J, Huang CRL, Xiang Y, Neretti N, et al. . Global regulation of nucleotide biosynthetic genes by c-Myc. PLoS One 2008;3:e2722. PubMed PMC

Huang F, Ni M, Chalishazar MD, Huffman KE, Kim J, Cai L, et al. . Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers. Cell Metab 2018;28:369–82.e5. PubMed PMC

Terunuma A, Putluri N, Mishra P, Mathé EA, Dorsey TH, Yi M, et al. . MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest 2014;124:398–412. PubMed PMC

Budczies J, Brockmöller SF, Müller BM, Barupal DK, Richter-Ehrenstein C, Kleine-Tebbe A, et al. . Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism. J Proteomics 2013;94:279–88. PubMed

Liao C, Glodowski CR, Fan C, Liu J, Mott KR, Kaushik A, et al. . Integrated metabolic profiling and transcriptional analysis reveals therapeutic modalities for targeting rapidly proliferating breast cancers. Cancer Res 2022;82:665–80. PubMed PMC

Eberhardy SR, Farnham PJ. Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. J Biol Chem 2002;277:40156–62. PubMed

Brès V, Yoshida T, Pickle L, Jones KA. SKIP interacts with c-Myc and menin to promote HIV-1 Tat transactivation. Mol Cell 2009;36:75–87. PubMed PMC

Bouchard C, Marquardt J, Brás A, Medema RH, Eilers M. Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO J 2004;23:2830–40. PubMed PMC

Kanazawa S, Soucek L, Evan G, Okamoto T, Peterlin BM. c-Myc recruits P-TEFb for transcription, cellular proliferation and apoptosis. Oncogene 2003;22:5707–11. PubMed

Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, et al. . c-Myc regulates transcriptional pause release. Cell 2010;141:432–45. PubMed PMC

Muthalagu N, Murphy DJ. Is oxidative stress MYC’s Achilles heel? Cell Death Differ 2018;25:1189–90. PubMed PMC

Chandriani S, Frengen E, Cowling VH, Pendergrass SA, Perou CM, Whitfield ML, et al. . A core MYC gene expression signature is prominent in basal-like breast cancer but only partially overlaps the core serum response. PLoS One 2009;4:e6693. PubMed PMC

Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 2015;1:417–25. PubMed PMC

Lynch M, Marinov GK. The bioenergetic costs of a gene, Proc Natl Acad Sci U S A 2015;112:15690–5. PubMed PMC

Traut TW. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 1994;140:1–22. PubMed

Lane AN, Fan TWM. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res 2015;43:2466–85. PubMed PMC

Curto R, Voit EO, Sorribas A, Cascante M. Mathematical models of purine metabolism in man. Math Biosci 1998;151:1–49. PubMed

Pillwein K, Chiba P, Knoflach A, Czermak B, Schuchter K, Gersdorf E, et al. . Purine metabolism of human glioblastoma in vivo. Cancer Res 1990;50:1576–9. PubMed

Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. PubMed

Braga TT, Forni MF, Correa-Costa M, Ramos RN, Barbuto JA, Branco P, et al. . Soluble uric acid activates the NLRP3 inflammasome. Sci Rep 2017;7:39884. PubMed PMC

Zrenner R, Stitt M, Sonnewald U, Boldt R. Pyrimidine and purine biosynthesis and degradation in plants. Annu Rev Plant Biol 2006;57:805–36. PubMed

Hsu TY-T, Simon LM, Neill NJ, Marcotte R, Sayad A, Bland CS, et al. . The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 2015;525:384–8. PubMed PMC

Mi H, Ebert D, Muruganujan A, Mills C, Albou LP, Mushayamaha T, et al. . PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API Nucleic Acids Res 2021;49:D394–403. PubMed PMC

Staals RHJ, Bronkhorst AW, Schilders G, Slomovic S, Schuster G, Heck AJR, et al. . Dis3-like 1: a novel exoribonuclease associated with the human exosome. EMBO J 2010;29:2358–67. PubMed PMC

Tomecki R, Kristiansen MS, Lykke-Andersen S, Chlebowski A, Larsen KM, Szczesny RJ, et al. . The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L. EMBO J 2010;29:2342–57. PubMed PMC

Puno MR, Weick EM, Das M, Lima CD. SnapShot: the RNA exosome. Cell 2019;179:282e1. PubMed

Moore MJ. Nuclear RNA turnover. Cell 2002;108:431–4. PubMed

Thomas MP, Liu X, Whangbo J, McCrossan G, Sanborn KB, Basar E, et al. . Apoptosis triggers specific, rapid, and global mRNA decay with 3′uridylated intermediates degraded by DIS3L2. Cell Rep 2015;11:1079–89. PubMed PMC

Fanidi A, Harrington EA, Evan GI. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 1992359:554–6. PubMed

Bissonnette RP, Echeverri F, Mahboubi A, Green DR. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 1992;359:552–4. PubMed

Yang E, van Nimwegen E, Zavolan M, Rajewsky N, Schroeder M, Magnasco M, et al. . Decay rates of human mRNAs: correlation with functional characteristics and sequence attributes. Genome Res 2003;13:1863–72. PubMed PMC

Weber MJ. Ribosomal RNA turnover in contact inhibited cells. Nat New Biol 1972;235:58–61. PubMed

Yi X, Tesmer VM, Savre-Train I, Shay JW, Wright WE. Both transcriptional and posttranscriptional mechanisms regulate human telomerase template RNA levels. Mol Cell Biol 1999;19:3989–97. PubMed PMC

Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, et al. . Global quantification of mammalian gene expression control. Nature 2011;473:337–42. PubMed

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. . The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012;2:401–4. PubMed PMC

Katsonis P, Lichtarge O. A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness. Genome Res 2014;24:2050–8. PubMed PMC

Makino DL, Baumgärtner M, Conti E. Crystal structure of an RNA-bound 11-subunit eukaryotic exosome complex. Nature 2017;495:70–5. PubMed

Yang W. Nucleases: diversity of structure, function and mechanism. Q Rev Biophys 2011;44:1–93. PubMed PMC

Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, et al. . c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell 2002;9:1031–44. PubMed

KC S, Cárcamo JM, Golde DW. Antioxidants prevent oxidative DNA damage and cellular transformation elicited by the over-expression of c-MYC. Mutat Res 2006;593:64–79. PubMed

Morrish F, Neretti N, Sedivy JM, Hockenbery DM. The oncogene c-Myc coordinates regulation of metabolic networks to enable rapid cell cycle entry. Cell Cycle 2008;7:1054–66. PubMed PMC

Harris CM, Massey V. The reaction of reduced xanthine dehydrogenase with molecular oxygen: reaction kinetics and measurement of superoxide radical. J Biol Chem 1997;272:8370–9. PubMed

Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer 2008;8:24–36. PubMed

Mathews CK. DNA synthesis as a therapeutic target: the first 65 years. FASEB J 2012;26:2231. 7. PubMed PMC

Eng WS, Hocková D, Špaček P, Janeba Z, West NP, Woods K, et al. . First crystal structures of Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase: complexes with GMP and pyrophosphate and with acyclic nucleoside phosphonates whose prodrugs have antituberculosis activity. J Med Chem 2015;58:4822–38. PubMed

Meerbrey KL, Hu G, Kessler JD, Roarty K, Li MZ, Fang JE, et al. . The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. Proc Natl Acad Sci U S A 2011;108:3665–70. PubMed PMC

Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. . Genes that mediate breast cancer metastasis to lung. Nature 2005;436:518–524. PubMed PMC

Spandidos A, Wang X, Wang H, Seed B. PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res 2010;38:D792–9. PubMed PMC

Putluri N, Shojaie A, Vasu VT, Nalluri S, Vareed SK, Putluri V, et al. . Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells. PLoS One;2011;6:e21417. PubMed PMC

Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J 2011;17:10–2.

Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods 20129:357–9. PubMed PMC

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15:550. PubMed PMC

Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr 2010;66:486–501. PubMed PMC

Soetaert K, Petzoldt T, Setzer RW. Solving differential equations in R: package deSolve. J Stat Softw 2010;33:1–25. PubMed

Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. . TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res 2016;44:e71. PubMed PMC

Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, et al. . Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci U S A 2007;104:20007–12. PubMed PMC

Thomas PD, Ebert D, Muruganujan A, Mushayahama T, Albou LP, Mi H. PANTHER: making genome-scale phylogenetics accessible to all. Protein Sci 2022;31:8–22. PubMed PMC