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.

中文翻译：

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MYC 通过乳腺癌的 RNA 衰变和核糖核苷酸分解代谢诱导致癌应激


MYC 的上调是癌症的一个标志，其中 MYC 驱动致癌基因表达并增加癌细胞转录组中的总 RNA 合成。尽管这种转录合成代谢促进了癌症的生长和存活，但人们对过量细胞 RNA 诱导的后果和代谢应激知之甚少。在此，我们发现 RNA 降解和下游核糖核苷酸分解代谢是 MYC 诱导癌细胞死亡的新机制。结合遗传学和代谢组学，我们发现 MYC 增加 RNA 通过细胞质外泌体的衰变，导致细胞毒性 RNA 分解代谢物和活性氧的积累。值得注意的是，肿瘤来源的外泌体突变消除了 MYC 诱导的细胞死亡，表明过量的 RNA 衰变可能对人类癌症有毒。一致，嘌呤挽救作为减轻 MYC 诱导的核糖核苷酸分解代谢的代偿途径，而嘌呤挽救的抑制剂会损害 MYC+ 肿瘤进展。总之，这些数据表明 MYC 诱导的 RNA 衰变是一种可以用于治疗的致癌应激。意义： MYC 是预后不良癌症最常见的致癌驱动因素，但对治疗抑制一直顽固。我们在 MYC+ 癌症中发现了一个新的漏洞，其中 MYC 通过过量的 RNA 衰变诱导细胞死亡。加剧下游核糖核苷酸分解代谢的疗法为 TNBC（三阴性乳腺癌）和其他 MYC 驱动的癌症提供了一种治疗上可处理的方法。