The spliceosome is a therapeutic vulnerability in MYC-driven cancer.
The spliceosome is a therapeutic vulnerability in MYC-driven cancer.
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DOI：
10.1038/nature14985
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发表时间：
2015-09-17
期刊：
影响因子：
64.8
通讯作者：
Westbrook TF
中科院分区：
文献类型：
--
作者：
Hsu TY;Simon LM;Neill NJ;Marcotte R;Sayad A;Bland CS;Echeverria GV;Sun T;Kurley SJ;Tyagi S;Karlin KL;Dominguez-Vidaña R;Hartman JD;Renwick A;Scorsone K;Bernardi RJ;Skinner SO;Jain A;Orellana M;Lagisetti C;Golding I;Jung SY;Neilson JR;Zhang XH;Cooper TA;Webb TR;Neel BG;Shaw CA;Westbrook TF
c-MYC（MYC）过表达或过度活化是人类癌症最常见的驱动因素之一。尽管深入研究，MYC癌基因仍然难以治疗抑制。MYC是一种转录因子，其许多促肿瘤发生功能归因于其调节基因表达程序的能力。值得注意的是，致癌MYC激活也已显示在许多组织和疾病背景中增加总RNA和蛋白质产生。虽然RNA和蛋白质产生的这种增加可能赋予癌细胞促肿瘤标志，但这种合成的提高也可能对MYC驱动的癌细胞产生新的或更高的负担，以正确处理这些大分子。在此，我们发现剪接体作为MYC驱动的癌症中致癌应激的新靶点。我们确定BUD 31作为MYC合成致死基因，并证明BUD 31是其组装和催化活性所需的核心剪接体的组成部分。与BUD 31相关的核心剪接体因子（SF 3B 1，U2 AF 1等）也是耐受致癌MYC所必需的。值得注意的是，MYC超活化诱导总前体mRNA合成的增加，表明核心剪接体处理前体mRNA的负担增加。与正常细胞相反，MYC超活化细胞中剪接体的部分抑制导致全局内含子保留、前mRNA成熟的广泛缺陷和许多基本细胞过程的失调。重要的是，体内剪接体的遗传或药理学抑制损害MYC依赖性乳腺癌的存活、致瘤性和转移倾向。总的来说，这些数据表明，致癌MYC赋予剪接的附带应力，剪接体的组分可能是侵袭性MYC驱动的癌症的治疗切入点。
c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein production may endow cancer cells with pro-tumor hallmarks, this elevation in synthesis may also generate new or heightened burden on MYC-driven cancer cells to properly process these macromolecules. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (SF3B1, U2AF1, and others) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.