Objective To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6. Design We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitroand in vivo. Results SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a β2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity. Conclusions SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6. Accession numbers The accession numbers for sequencing data are SRP111763 and SRP111797.

中文翻译：

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促进肿瘤进展的SRSF6调节的选择性剪接为结直肠癌提供了治疗靶点

目的研究剪接因子SRSF6在结直肠癌（CRC）进展中的分子功能，并通过靶向SRSF6发现癌症治疗的候选化学物质。设计 我们对 311 个 CRC 样本、癌症基因组图谱和基因表达综合 (GEO) 数据库中的 SRSF6 表达进行了综合分析。CRC 中 SRSF6 的功能分析在体外和体内进行。SRSF6 调控的选择性剪接（AS）及其结合基序通过下一代 RNA 测序和 RNA 免疫沉淀测序（RIP-seq）进行鉴定，并通过凝胶移位和小基因报告基因检测进行验证。研究了 ZO-1 外显子 23 AS 在体外和体内介导 SRSF6 的功能。基于特定领域角色的分析，SRSF6 靶向抑制剂在 4855 种 FDA 批准的药物中被从头虚拟筛选中发现，并在体外和体内评估了其抗肿瘤作用。结果 SRSF6 在 CRC 样本中经常上调并与不良预后相关，这促进了体外和体内的增殖和转移。我们确定了 SRSF6 调节的 AS 目标并发现了 SRSF6 结合基序。特别是，SRSF6 通过直接结合外显子 23 中的基序来调节 ZO-1 异常剪接以发挥致癌基因的作用。基于 SRSF6 RRM2 结构域在调节 AS 和生物学功能中起关键作用的结果，茚达特罗是一种被批准用于慢性阻塞性肺疾病治疗的 β2-肾上腺素能受体激动剂，被确定为 SRSF6 的抑制剂，以抑制 CRC 致瘤性。结论 SRSF6 通过调节 AS 在介导 CRC 进展中发挥重要作用，茚达特罗通过靶向 SRSF6 被重新定位为抗肿瘤药物。登录号 测序数据的登录号是 SRP111763 和 SRP111797。