Splicing Regulator p54nrb/Non-POU Domain-Containing Octamer-Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box-Dependent Interacting Protein 1 in Hepatocellular Carcinoma
Splicing Regulator p54nrb/Non-POU Domain-Containing Octamer-Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box-Dependent Interacting Protein 1 in Hepatocellular Carcinoma
复制标题
剪接调节因子 p54 nrb /非 POU 结构域 - 含有八聚体 - 结合蛋白通过 MYC Box 的致癌异构体开关 - 肝细胞癌中依赖性相互作用蛋白 1 增强癌发生
DOI：
10.1002/hep.31062
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发表时间：
2020-03-25
期刊：
影响因子：
13.5
通讯作者：
He, Xianghuo
中科院分区：
文献类型：
--
作者：
Hu, Zhixiang;Dong, Liangqing;He, Xianghuo
选择性剪接（Alternative splicing，AS）是增加肿瘤转录组多样性和复杂性的关键步骤。最近的证据表明，AS在癌症中的作用越来越重要。尽管如此，肝细胞癌（HCC）中AS及其失调的潜在机制仍然难以捉摸。在这里，我们报告说，RNA结合蛋白p54（nrb）/非POU域含有八聚体结合蛋白（NONO）的表达经常增加，在HCC患者，并与不良outcomes.Approach和结果NONO敲低显着取消肝癌细胞增殖，迁移和肿瘤形成。RNA测序显示，NONO调节MYC盒依赖性相互作用蛋白1（或桥接整合子1 [BIN 1];也称为两性物理蛋白2 3 P9）外显子12 a剪接。在正常肝脏中，BIN 1产生一个短的同种型（BIN 1-S），通过抑制c-Myc与靶基因启动子的结合来作为肿瘤抑制因子。在HCC中，NONO高度上调并产生长同种型（BIN 1-L，其包含外显子12 a）而不是BIN 1-S。高水平的BIN 1-L通过与蛋白质Polo样激酶1结合来促进致癌作用，从而通过防止遍在蛋白/蛋白酶体依赖性cullin 3降解来增强其稳定性。进一步的分析表明，NONO通过与DExH盒解旋酶9（DHX 9）和剪接因子脯氨酸和谷氨酰胺丰富（SFPQ）的相互作用促进BIN 1外显子12 a的包含。值得注意的是，DHX 9-NONO-SFPQ的频繁共表达观察到在HCC患者中。结论两者合计，我们的研究结果确定DHX 9-NONO-SFPQ复合物作为一个关键的调节器操纵致癌剪接开关的BIN 1和作为一个候选治疗靶点在肝癌。
Background and Aims Alternative splicing (AS) is a key step that increases the diversity and complexity of the cancer transcriptome. Recent evidence has highlighted that AS has an increasingly crucial role in cancer. Nonetheless, the mechanisms underlying AS and its dysregulation in hepatocellular carcinoma (HCC) remain elusive. Here, we report that the expression of RNA-binding protein p54(nrb)/non-POU domain-containing octamer-binding protein (NONO) is frequently increased in patients with HCC and is associated with poor outcomes.Approach and Results Knockdown of NONO significantly abolished liver cancer cell proliferation, migration, and tumor formation. RNA-sequencing revealed that NONO regulates MYC box-dependent interacting protein 1 (or bridging integrator 1 [BIN1]; also known as amphiphysin 2 3P9) exon 12a splicing. In the normal liver, BIN1 generates a short isoform (BIN1-S) that acts as a tumor suppressor by inhibiting the binding of c-Myc to target gene promoters. In HCC, NONO is highly up-regulated and produces a long isoform (BIN1-L, which contains exon 12a) instead of BIN1-S. High levels of BIN1-L promote carcinogenesis by binding with the protein polo-like kinase 1 to enhance its stability through the prevention of ubiquitin/proteasome-dependent cullin 3 degradation. Further analysis revealed that NONO promotes BIN1 exon 12a inclusion through interaction with DExH-box helicase 9 (DHX9) and splicing factor proline and glutamine-rich (SFPQ). Notably, frequent coexpression of DHX9-NONO-SFPQ is observed in patients with HCC.Conclusions Taken together, our findings identify the DHX9-NONO-SFPQ complex as a key regulator manipulating the oncogenic splicing switch of BIN1 and as a candidate therapeutic target in liver cancer.