RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo-Yap Pathway.
The Hippo-Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARγ as a regulator of the Hippo-Yap pathway in colorectal tumorigenesis and metastasis. RARγ is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARγ drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo Mechanistically, RARγ controlled Hippo-Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARγ expression correlated with overall survival outcomes and expression of critical Hippo-Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARγ as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo-Yap pathway, with potential implications for new approaches to colorectal cancer therapy. Cancer Res; 76(13); 3813-25. ©2016 AACR.
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Peng-Da
PD
Guo
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Xing-Xing
XX
Lu
Pathology Center and Department of Pathology, Soochow University, Suzhou, China. The First Affiliated Hospital of Soochow University, Suzhou, China.
Wen-Juan
WJ
Gan
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Xiu-Ming
XM
Li
Pathology Center and Department of Pathology, Soochow University, Suzhou, China. The First Affiliated Hospital of Soochow University, Suzhou, China.
Xiao-Shun
XS
He
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Shen
S
Zhang
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Qing-Hua
QH
Ji
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Feng
F
Zhou
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Yue
Y
Cao
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Jing-Ru
JR
Wang
Pathology Center and Department of Pathology, Soochow University, Suzhou, China. wuhua@suda.edu.cn jianmingli@suda.edu.cn.
Jian-Ming
JM
Li
Pathology Center and Department of Pathology, Soochow University, Suzhou, China. wuhua@suda.edu.cn jianmingli@suda.edu.cn.
Hua
H
Wu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000090683:Hippo Signaling Pathway; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins; D000097768:Retinoic Acid Receptor gamma
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000097768:Retinoic Acid Receptor gamma; C088374:YAP1 protein, human; C092745:LATS1 protein, human