Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation
Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation
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DOI：
10.1172/jci125022
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发表时间：
2019-11-01
影响因子：
15.9
通讯作者：
Park, Ben Ho
中科院分区：
文献类型：
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作者：
Dalton, W. Brian;Helmenstine, Eric;Park, Ben Ho
剪接体基因SF3B1的癌症相关突变产生一种新形态蛋白，在数百个基因中产生异常的mRNA剪接，但这种错误剪接的生物学和治疗后果尚不清楚。我们提供的证据表明，突变体SF3B1的异常剪接改变了人类细胞的转录组、蛋白质组和代谢组，导致剪接错误相关的代谢基因下调，线粒体呼吸减少，丝氨酸合成途径受到抑制。我们还发现突变体SF3B1诱导非必需氨基酸丝氨酸被剥夺的脆弱性，这是通过错误剪接相关的丝氨酸合成途径酶PHGDH下调介导的。这种脆弱性在体外和体内都表现出来，因为小鼠饮食中限制丝氨酸和甘氨酸能够抑制SF3B1（MUT）异种移植物的生长。这些发现描述了SF3B1突变在能量代谢改变中的作用，并提供了针对SF3B1（MUT）癌症的新治疗策略。
Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1(MUT) xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1(MUT) cancers.