SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing
SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing
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DOI：
10.1016/j.celrep.2017.11.091
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发表时间：
2017-12-19
期刊：
影响因子：
8.8
通讯作者：
Feng, Ying
中科院分区：
文献类型：
--
作者：
Chen, Linlin;Luo, Chunling;Feng, Ying
调节失调的选择性剪接事件与许多类型的癌症有关，但其潜在的分子机制仍不清楚。在这里，我们观察到剪接因子SRSF1通过特异性结合和促进其包含来调节DBF4B外显子6的剪接。含有外显子6的异构体(DBF4B-FL)的敲除显著抑制了结肠癌细胞在体外和小鼠体内的致瘤潜力，SRSF1失活表型使DBF4B-FL耗尽。DBF4B-FL和SRSF1是癌细胞增殖和维持基因组稳定性所必需的。过表达DBF4B-FL可以保护SRSF1基因敲除引起的DNA损伤，并挽救SRSF1缺失细胞的生长缺陷。在临床结直肠癌样本中，DBF4B外显子6包涵体增加与SRSF1上调平行。综上所述，我们的发现确认SRSF1是结肠癌中DBF4B前mRNA剪接异常的关键调节因子，可能具有临床意义，可以作为癌症患者的候选预后因素。
Dysregulated alternative splicing events have been implicated in many types of cancer, but the underlying molecular mechanisms remain unclear. Here, we observe that the splicing factor SRSF1 regulates DBF4B exon6 splicing by specifically binding and promoting its inclusion. Knockdown of the exon6-containing isoform (DBF4B-FL) significantly inhibits the tumorigenic potential of colon cancer cells in vitro and in mice, and SRSF1 inactivation phenocopies DBF4B-FL depletion. DBF4B-FL and SRSF1 are required for cancer cell proliferation and for the maintenance of genomic stability. Overexpression of DBF4B-FL can protect against DNA damage induced by SRSF1 knockdown and rescues growth defects in SRSF1-depleted cells. Increased DBF4B exon6 inclusion parallels SRSF1 upregulation in clinical colorectal cancer samples. Taken together, our findings identify SRSF1 as a key regulator of DBF4B pre-mRNA splicing dysregulation in colon cancer, with possible clinical implications as candidate prognostic factors in cancer patients.