PRAME Augments K63-Linked Ubiquitination and Stabilization of METTL3 to Promote Lung Adenocarcinoma Metastasis.

Metastasis is the primary cause of mortality in cancer including lung adenocarcinoma (LUAD), yet the underlying mechanisms remain incompletely understood. Preferentially expressed antigen of melanoma (PRAME), a cancer-testis antigen, displays context-dependent functions across malignancies, but its biological role in LUAD metastasis has not been clearly defined. Here, we demonstrate that the significantly upregulated PRAME in metastatic LUAD directly interacts with the m6A methyltransferase METTL3 and promotes its K63-linked non-proteolytic ubiquitination. This modification occurs at lysine 235 of METTL3, increases its protein stability and facilitates METTL3 interaction with METTL14 and WTAP. Consequently, m6A modification of TGFB2 mRNA and activation of the TGF-β signaling pathway are enhanced, which is essential for PRAME-driven pro-metastatic effects both in vitro and in vivo. Clinically, PRAME expression positively correlates with METTL3 protein abundance and TGF-β pathway activation, and is robustly associated with poor clinical outcomes. Taken together, our findings identify K63-linked ubiquitination as a previously unrecognized post-translational modification of METTL3 and underscore the importance of the PRAME/METTL3/TGF-β axis in LUAD metastasis, providing mechanistic insights and potential therapeutic targets for this malignancy.