Mutual inhibition between YAP and SRSF1 maintains long non-coding RNA, Malat1-induced tumourigenesis in liver cancer.
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.
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Jiayi
J
Wang
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.
Hongmei
H
Wang
Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Yue
Y
Zhang
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Ni
N
Zhen
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Li
L
Zhang
School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Yongxia
Y
Qiao
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Wenhao
W
Weng
Faculty of Medical Laboratory Science, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Xiangfan
X
Liu
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Lifang
L
Ma
Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Weifan
W
Xiao
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Wenjun
W
Yu
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Qinghua
Q
Chu
Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Qiuhui
Q
Pan
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address: sunfenyong@126.com.
Fenyong
F
Sun
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000091082:Angiomotins; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
C423985:AMOT protein, human; D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; C557041:MALAT1 long non-coding RNA, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051176:beta Catenin; D000068103:Serine-Arginine Splicing Factors
Angiomotin (AMOT); Hippo/YAP pathway; Promoter; RNA stability; Wnt pathway