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

Nature Communications

Jian Han¹  Yaokai Ye²  Xingui Wu³  Jun Li³  Junchao Cai⁴  Yukai He⁵  Jueheng Wu⁶  Han Tian⁶  Chenying Liu⁶  Tianyu Tao⁶  Xia Yang⁶  Shujun Liang⁶  Xuwei Chen⁶  Rong Lian⁶  Wei Li⁶  Mengfeng Li⁷  Yun Li⁸ 

[1] Cancer Institute, Southern Medical University, 510515, Guangzhou, Guangdong, China;Clinical Medicine, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China;Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China;Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China;Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, 510080, Guangzhou, China;Department of Medicine and Georgia Cancer Center, Medical College of Georgia, Augusta University, 30912, Augusta, GA, USA;Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China;Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China;Cancer Institute, Southern Medical University, 510515, Guangzhou, Guangdong, China;Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, 510632, Guangzhou, Guangdong, China;

DOI  :  10.1038/s41467-020-18929-0

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY