Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization.,Cancer Discovery

当前位置： X-MOL 学术 › Cancer Discov. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization.
Cancer Discovery ( IF 29.7 ) Pub Date : 2020-06-01 , DOI: 10.1158/2159-8290.cd-19-1330
Zhaoqi Liu _{1,

2} , Akihide Yoshimi ₃ , Jiguang Wang ₄ , Hana Cho ₃ , Stanley Chun-Wei Lee ₃ , Michelle Ki ₃ , Lillian Bitner ₃ , Timothy Chu _{1,

2} , Harshal Shah ₃ , Bo Liu ₃ , Anthony R Mato ₅ , Peter Ruvolo ₆ , Giulia Fabbri ₇ , Laura Pasqualucci _{7,

8} , Omar Abdel-Wahab _{3,

5} , Raul Rabadan _{1,

2}

Affiliation

Although mutations in the gene encoding the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here, we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3′ splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the protein phosphatase 2A (PP2A) subunit PPP2R5A, increasing MYC S62 and BCL2 S70 phosphorylation which, in turn, promotes MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis, elucidating a therapeutic approach to aberrant splicing by mutant SF3B1. Significance: Here, we identify that mutations in SF3B1 , the most commonly mutated splicing factor gene across cancers, alter splicing of a specific subunit of the PP2A serine/threonine phosphatase complex to confer post-translational MYC and BCL2 activation, which is therapeutically intervenable using an FDA-approved drug. See related commentary by O'Connor and Narla, [p. 765][1] . This article is highlighted in the In This Issue feature, [p. 747][2] [1]: /lookup/volpage/10/765?iss=6 [2]: /lookup/volpage/10/747?iss=6

中文翻译：

RNA 剪接因子 SF3B1 的突变通过 MYC 稳定促进肿瘤发生。

尽管编码 RNA 剪接因子 SF3B1 的基因突变在多种癌症中很常见，但对其功能影响和治疗依赖性知之甚少。在这里，我们表征了 98 个肿瘤和 12 个具有 SF3B1 热点突变的同基因细胞系，确定了数百个对不同癌症类型常见和特异性的神秘 3' 剪接位点。监管网络分析显示，最常见的 SF3B1 突变通过人类和小鼠细胞中保守的效应激活 MYC。SF3B1 突变促进编码蛋白磷酸酶 2A (PP2A) 亚基 PPP2R5A 的转录物的衰变，增加 MYC S62 和 BCL2 S70 的磷酸化，从而分别促进 MYC 蛋白的稳定性和损害细胞凋亡。基因 PPP2R5A 恢复或药理学 PP2A 激活损害 SF3B1 突变肿瘤发生，阐明突变体 SF3B1 异常剪接的治疗方法。意义：在这里，我们发现 SF3B1 中的突变（癌症中最常见的突变剪接因子基因）改变了 PP2A 丝氨酸/苏氨酸磷酸酶复合物的特定亚基的剪接以赋予翻译后 MYC 和 BCL2 激活，这在治疗上可使用FDA批准的药物。参见 O'Connor 和 Narla 的相关评论，[p. 765][1]。本文在 In This Issue 功能中突出显示，[p. 747][2] [1]:/lookup/volpage/10/765?iss=6 [2]:/lookup/volpage/10/747?iss=6 改变 PP2A 丝氨酸/苏氨酸磷酸酶复合物的特定亚基的剪接以赋予翻译后 MYC 和 BCL2 激活，这可以使用 FDA 批准的药物进行治疗干预。参见 O'Connor 和 Narla 的相关评论，[p. 765][1]。本文在 In This Issue 功能中突出显示，[p. 747][2] [1]:/lookup/volpage/10/765?iss=6 [2]:/lookup/volpage/10/747?iss=6 改变 PP2A 丝氨酸/苏氨酸磷酸酶复合物的特定亚基的剪接以赋予翻译后 MYC 和 BCL2 激活，这可以使用 FDA 批准的药物进行治疗干预。参见 O'Connor 和 Narla 的相关评论，[p. 765][1]。本文在 In This Issue 功能中突出显示，[p. 747][2] [1]:/lookup/volpage/10/765?iss=6 [2]:/lookup/volpage/10/747?iss=6

更新日期：2020-06-01

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11