The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis

Tongde Du, Hongchang Li, Yongsheng Fan, Lin Yuan, Xiaodan Guo, Qiong Zhu, Yuying Yao, Xin Li, Chunlei Liu, Xinhe Yu, Zhaofei Liu, Chun-Ping Cui, Chuanchun Han () and Lingqiang Zhang ()
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Tongde Du: Beijing Institute of Lifeomics
Hongchang Li: Beijing Institute of Lifeomics
Yongsheng Fan: Dalian Medical University
Lin Yuan: Peking University Health Science Center
Xiaodan Guo: Dalian Medical University
Qiong Zhu: Beijing Institute of Lifeomics
Yuying Yao: Beijing Institute of Lifeomics
Xin Li: Chinese PLA General Hospital
Chunlei Liu: Chinese PLA General Hospital
Xinhe Yu: Peking University Health Science Center
Zhaofei Liu: Peking University Health Science Center
Chun-Ping Cui: Beijing Institute of Lifeomics
Chuanchun Han: Dalian Medical University
Lingqiang Zhang: Beijing Institute of Lifeomics

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract The deubiquitylase OTUD3 plays a suppressive role in breast tumorigenesis through stabilizing PTEN protein, but its role in lung cancer remains unclear. Here, we demonstrate that in vivo deletion of OTUD3 indeed promotes breast cancer development in mice, but by contrast, it slows down KrasG12D-driven lung adenocarcinoma (ADC) initiation and progression and markedly increases survival in mice. Moreover, OTUD3 is highly expressed in human lung cancer tissues and its higher expression correlates with poorer survival of patients. Further mechanistic studies reveal that OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein GRP78. Knockdown of OTUD3 results in a decrease in the level of GRP78 protein, suppression of cell growth and migration, and tumorigenesis in lung cancer. Collectively, our results reveal a previously unappreciated pro-oncogenic role of OTUD3 in lung cancer and indicate that deubiquitylases could elicit tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.

Date: 2019
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DOI: 10.1038/s41467-019-10824-7

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