Mutual inhibition between YAP and SRSF1 maintains long non-coding RNA, Malat1-induced tumourigenesis in liver cancer

• Published in: Cellular signalling Vol. 26; no. 5; pp. 1048 - 1059
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-05-2014
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Angiomotin (AMOT); Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; beta Catenin - metabolism; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Transformation, Neoplastic; HEK293 Cells; Hep G2 Cells; Hippo/YAP pathway; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Membrane Proteins - metabolism; Mice; Mice, Nude; Microfilament Proteins; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphoproteins - metabolism; Promoter; Promoter Regions, Genetic; RNA stability; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Serine-Arginine Splicing Factors; Transcription Factor 4; Transcription Factors - metabolism; Transcription, Genetic; Transplantation, Heterologous; Up-Regulation; Wnt pathway; RNA stability; lncRNA; Hippo/YAP pathway; IHC; Wnt pathway; SRSF1; TMA; YAP; HCC; ChIP; Promoter; MALAT1; IF; Angiomotin (AMOT)
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2014.01.022

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.
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•YAP up-regulates Malat1 via co-occupancy with TCF/β-catenin on the core promoter.•SRSF1 plays an inhibitory role on the stability of Malat1 in liver cancer cells.•YAP promotes SRSF1 binding to Angiomotin, and impairs their nuclear retention.•Higher expression of YAP correlates with lower SRSF1 nuclear accumulation.•Overexpression of YAP combined with knockdown of SRSF1 enhances tumourigenicity.