Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours

Ze Rui Wu, Lichong Yan, Yan Ting Liu, Lei Cao, Yu Hang Guo, Yong Zhang, Hong Yao, Lin Cai, Han Bing Shang, Wei Wei Rui, Gang Yang, Xiao Biao Zhang, Hao Tang, Yu Wang, Jin Yan Huang, Yong Xu Wei, Wei Guo Zhao, Bing Su () and Zhe Bao Wu ()
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Ze Rui Wu: Shanghai Jiao Tong University School of Medicine
Lichong Yan: Shanghai Jiao Tong University School of Medicine
Yan Ting Liu: Shanghai Jiao Tong University School of Medicine
Lei Cao: Capital Medical University
Yu Hang Guo: First Affiliated Hospital of Wenzhou Medical University
Yong Zhang: Shanghai Jiao Tong University School of Medicine
Hong Yao: Shanghai Jiao Tong University School of Medicine
Lin Cai: First Affiliated Hospital of Wenzhou Medical University
Han Bing Shang: Shanghai Jiao Tong University School of Medicine
Wei Wei Rui: Shanghai Jiao Tong University School of Medicine
Gang Yang: The First Affiliated Hospital of Chongqing Medical University
Xiao Biao Zhang: Fudan University
Hao Tang: Shanghai Jiao Tong University School of Medicine
Yu Wang: Shanghai Jiao Tong University School of Medicine
Jin Yan Huang: Shanghai Jiao Tong University School of Medicine
Yong Xu Wei: Shanghai Jiao Tong University School of Medicine
Wei Guo Zhao: Shanghai Jiao Tong University School of Medicine
Bing Su: Shanghai Jiao Tong University School of Medicine
Zhe Bao Wu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours.

Date: 2018
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DOI: 10.1038/s41467-018-06853-3

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