Reduced symmetric dimethylation stabilizes vimentin and promotes metastasis in MTAP‐deficient lung cancer. (29th June 2022)

• Record Type: Journal Article
• Authors: Chang, Wen‐Hsin; Chen, Yi‐Ju; Hsiao, Yi‐Jing; Chiang, Ching‐Cheng; Wang, Chia‐Yu; Chang, Ya‐Ling; Hong, Qi‐Sheng; Lin, Chien‐Yu; Lin, Shr‐Uen; Chang, Gee‐Chen; Chen, Hsuan‐Yu; Chen, Yu‐Ju; Chen, Ching‐Hsien; Yang, Pan‐Chyr; Yu, Sung‐Liang
• Is Part Of: EMBO reports. Volume 23:Number 8(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-29
• Subjects: Methylproteome -- Methylthioadenosine (MTA) -- Post‐translational modification (PTM) -- Protein arginine methyltransferase 5 (PRMT5) -- Symmetric dimethylarginine (sDMA); Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202154265
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell‐based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression‐free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP‐deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)‐mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl‐protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP‐deficient cells, lower sDMA modification prevents ubiquitination‐mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post‐translational regulation. Synopsis: Repression of MTAP‐dependent symmetric dimethylation mediated by PRMT5 increases vimentin protein stability and leads to invasion and metastasis in MTAP‐deficient lung cancer. MTAP loss promotes lung cancer metastasis. MTA accumulation in MTAP‐deficient cancer cells inhibits PRMT5‐mediated symmetric dimethylation on arginine residues of vimentin. Vimentin is destabilized by PRMT5‐mediated symmetric dimethylation. Reduced dimethylation and stabilization of vimentin in MTAP‐deficient cancer cells contributes to invasion and metastasis. Abstract : Repression of MTAP‐dependent symmetric dimethylation mediated by PRMT5 increases vimentin protein stability and leads to invasion and metastasis in MTAP‐deficient lung cancer.