Wang Jiayi, Wang Hongmei, Zhang Yue, Zhen Ni, Zhang Li, Qiao Yongxia, Weng Wenhao, Liu Xiangfan, Ma Lifang, Xiao Weifan, Yu Wenjun, Chu Qinghua, Pan Qiuhui, Sun Fenyong
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China; Institute of Bioengineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
Cell Signal. 2014 May;26(5):1048-59. doi: 10.1016/j.cellsig.2014.01.022. Epub 2014 Jan 25.
Emerging studies have revealed that Malat1 is overexpressed in many malignant diseases, including liver cancer, and contributes to enhancing cell migration or facilitating proliferation. However, the mechanism underlying its regulation has largely remained elusive. Here, we characterised the oncoprotein Yes-associated protein (YAP), which up-regulated metastasis-associated lung adenocarcinoma transcript 1 (Malat1) expression at both transcriptional and post-transcriptional levels, whereas serine/arginine-rich splicing factor 1 (SRSF1) played an opposing role. SRSF1 inhibited YAP activity by preventing its co-occupation with TCF/β-catenin on the Malat1 promoter. In contrast, overexpression of YAP impaired the nuclear retention of both SRSF1 and itself via an interaction with Angiomotin (AMOT). This effect removed the inhibitory role of SRSF1 on Malat1 in the nucleus. Furthermore, higher expression of YAP was consistent with a lower SRSF1 nuclear accumulation in human liver cancer tissues. We also revealed that overexpression of YAP combined with a knockdown of SRSF1 resulted in conspicuously enhanced transwell cell mobility, accelerated tumour growth rate, and loss of body weight in a tail vein-injected mouse models. Taken together, these data provided a novel mechanism underlying the balance between SRSF1, YAP and Malat1 and uncovered a new role of YAP in regulating long non-coding RNA (lncRNA). Thus, disrupting the interaction between YAP and SRSF1 may serve as a crucial therapeutic method in liver cancer.
新兴研究表明，转移相关肺腺癌转录本1（Malat1）在包括肝癌在内的许多恶性疾病中均有过表达，并有助于增强细胞迁移或促进增殖。然而，其调控的潜在机制在很大程度上仍不清楚。在此，我们对癌蛋白Yes相关蛋白（YAP）进行了表征，YAP在转录和转录后水平上调了Malat1的表达，而富含丝氨酸/精氨酸的剪接因子1（SRSF1）则发挥相反作用。SRSF1通过阻止YAP与Malat1启动子上的TCF/β-连环蛋白共同占据来抑制YAP活性。相反，YAP的过表达通过与血管动蛋白（AMOT）相互作用损害了SRSF1及其自身的核滞留。这种作用消除了SRSF1在细胞核中对Malat1的抑制作用。此外，在人类肝癌组织中，YAP的高表达与SRSF1核内积累减少一致。我们还发现，在尾静脉注射的小鼠模型中，YAP过表达与SRSF1敲低相结合导致明显增强的Transwell细胞迁移能力、加速的肿瘤生长速度和体重减轻。综上所述，这些数据提供了一种SRSF1、YAP和Malat1之间平衡的新机制，并揭示了YAP在调节长链非编码RNA（lncRNA）中的新作用。因此，破坏YAP与SRSF1之间的相互作用可能成为肝癌治疗的关键方法。
