Repression of PRMT5-mediated dimethylation stabilizes vimentin and promotes metastasis in MTAP-loss lung cancer

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, and patients with low MTAP expression displayed worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduced the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. Vimentin was revealed as a novel dimethyl-protein with less dimethylation level in response to MTAP loss. The sDMA modification on vimentin reduces its protein abundance and trivially affects its filamentous structure. In MTAP-loss cells, lower sDMA level prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin, contributing to cell invasion. This inverse association of the MTAP/PRMT5 axis with vimentin proteins was clinically corroborated. Taken together, we propose a novel mechanism of vimentin post-translational regulation and provide new insights in metastasis.