A splicing isoform of TEAD4 attenuates the Hippo-YAP signalling to inhibit tumour proliferation.
Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signalling, a key pathway that regulates cell proliferation and organ size, is under control of a splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signalling, undergoes alternative splicing facilitated by the tumour suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. TEAD4-S is located in both the nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumour growth in xenograft mouse models. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether, these data reveal a splicing switch that serves to fine tune the Hippo-YAP pathway.
Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
Yangfan
Y
Qi
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Jing
J
Yu
Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
Wei
W
Han
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Xiaojuan
X
Fan
State Key Lab of Molecular Oncology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China.
Haili
H
Qian
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Huanhuan
H
Wei
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Yi-Hsuan S
YH
Tsai
Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
Jinyao
J
Zhao
Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
Wenjing
W
Zhang
Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
Quentin
Q
Liu
Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
Songshu
S
Meng
Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
Yang
Y
Wang
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Zefeng
Z
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; C473692:RBM4 protein, human; D016601:RNA-Binding Proteins; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases