AKT-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent Vimentin degradation

Han Tian, Rong Lian, Yun Li, Chenying Liu, Shujun Liang, Wei Li, Tianyu Tao, Xingui Wu, Yaokai Ye, Xia Yang, Jian Han, Xuwei Chen, Jun Li, Yukai He, Mengfeng Li, Jueheng Wu () and Junchao Cai ()
Additional contact information
Han Tian: Sun Yat-sen University
Rong Lian: Sun Yat-sen University
Yun Li: Jinan University
Chenying Liu: Sun Yat-sen University
Shujun Liang: Sun Yat-sen University
Wei Li: Sun Yat-sen University
Tianyu Tao: Sun Yat-sen University
Xingui Wu: Sun Yat-sen University
Yaokai Ye: Clinical Medicine, Zhongshan School of Medicine, Sun Yat-sen University
Xia Yang: Sun Yat-sen University
Jian Han: Southern Medical University
Xuwei Chen: Sun Yat-sen University
Jun Li: Sun Yat-sen University
Yukai He: Augusta University
Mengfeng Li: Sun Yat-sen University
Jueheng Wu: Sun Yat-sen University
Junchao Cai: Sun Yat-sen University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Despite the importance of AKT overactivation in tumor progression, results from clinical trials of various AKT inhibitors remain suboptimal, suggesting that AKT-driven tumor metastasis needs to be further understood. Herein, based on long non-coding RNA (lncRNA) profiling induced by active AKT, we identify that VAL (Vimentin associated lncRNA, LINC01546), which is directly induced by AKT/STAT3 signaling, functions as a potent pro-metastatic molecule and is essential for active AKT-induced tumor invasion, metastasis and anoikis resistance in lung adenocarcinoma (LAD). Impressively, chemosynthetic siRNAs against VAL shows great therapeutic potential in AKT overactivation-driven metastasis. Interestingly, similar to activated AKT in LAD cells, although unable to induce epithelial-mesenchymal transition (EMT), VAL exerts potent pro-invasive and pro-metastatic effects through directly binding to Vimentin and competitively abrogating Trim16-depedent Vimentin polyubiquitination and degradation. Taken together, our study provides an interesting demonstration of a lncRNA-mediated mechanism for active AKT-driven EMT-independent LAD metastasis and indicates the great potential of targeting VAL or Vimentin stability as a therapeutic approach.

Date: 2020
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DOI: 10.1038/s41467-020-18929-0

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