SRSF1-Regulated Alternative Splicing in Breast Cancer.
SRSF1-Regulated Alternative Splicing in Breast Cancer.
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DOI：
10.1016/j.molcel.2015.09.005
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发表时间：
2015-10-01
期刊：
影响因子：
16
通讯作者：
Krainer AR
中科院分区：
文献类型：
--
作者：
Anczuków O;Akerman M;Cléry A;Wu J;Shen C;Shirole NH;Raimer A;Sun S;Jensen MA;Hua Y;Allain FH;Krainer AR
剪接因子SRSF1在人类乳腺肿瘤中上调，其过表达促进乳腺细胞的转化。利用RNA - seq，我们在模拟与乳腺癌相关环境的器官型三维MCF - 10A细胞培养物中鉴定了SRSF1调控的可变剪接（AS）靶点。我们鉴定并验证了数百个内源性SRSF1调控的AS事件。对SRSF1结合基序的从头发现调和了先前基序分析中的差异。利用贝叶斯模型，我们确定了SRSF1结合对盒式外显子的位置效应：靠近5′剪接位点的结合通常促进外显子包含，而靠近3′剪接位点的结合促进外显子跳跃或包含。最后，我们鉴定了在人类肿瘤中失调的SRSF1调控的AS事件；过表达一种这样的异构体，即包含外显子9的CASC4，增加了腺泡大小和增殖，并减少了凋亡，部分重现了SRSF1的致癌作用。因此，我们揭示了SRSF1的正负调控机制以及致癌的AS事件，这些事件代表了治疗开发的潜在靶点。
Splicing factor SRSF1 is upregulated in human breast tumors, and its overexpression promotes transformation of mammary cells. Using RNA-seq, we identified SRSF1-regulated alternative splicing (AS) targets in organotypic three-dimensional MCF-10A cell cultures that mimic a context relevant to breast cancer. We identified and validated hundreds of endogenous SRSF1-regulated AS events. De-novo discovery of the SRSF1 binding motif reconciled discrepancies in previous motif analyses. Using a Bayesian model, we determined positional effects of SRSF1 binding on cassette exons: binding close to the 5′ splice site generally promoted exon inclusion, whereas binding near the 3′ splice site promoted either exon skipping or inclusion. Finally, we identified SRSF1-regulated AS events deregulated in human tumors; overexpressing one such isoform, exon-9-included CASC4, increased acinar size and proliferation, and decreased apoptosis, partially recapitulating SRSF1's oncogenic effects. Thus, we uncovered SRSF1 positive and negative regulatory mechanisms, and oncogenic AS events that represent potential targets for therapeutics development.