Tiam1 methylation by NSD2 promotes Rac1 signaling activation and cancer metastasis

Metastasis is the key cause of failure of cancer therapy or mortality, but targeting metastatic seeding and colonization remains an unresolved challenge. Here, we report a novel molecular event in cancer metastasis mediated by NSD2/Rac1 signaling and provide a detailed mechanistic investigation of cancer metastasis. We found that NSD2, a histone methyltransferase responsible for di-methylating histone 3 at lysine 36, was overexpressed in metastatic tumors, and overexpressed NSD2 enhanced tumor metastasis both in vitro and in vivo. We further investigated that NSD2 promoted tumor metastasis by activating the Rac1 signaling pathway. Mechanistically, NSD2 methylated Tiam1, a guanine nucleotide exchange factor that facilitates GDP-Rac1 to GTP-Rac1 transition at K724. We demonstrated that Tiam1 K724 methylation plays a crucial role in Tiam1 activation and GDP-Rac1 to GTP-Rac1 transition. Specifically, we identified that Tiam1 K724 methylation could be a predictive factor in cancer prognosis, and we demonstrated that pharmacological blocking of Tiam1 K724 methylation by employing a transmembrane peptide inhibited tumor metastasis both in vitro and in vivo. Thus, NSD2-methylated Tiam1 promoted Rac1 signaling activation and cancer metastasis, which might provide novel insights into tumor metastasis inhibition. Overall design: To investigate why NSD2 promotes cancer metastasis, we performed another RNA-seq analysis to identify the altered genes and signaling pathways between NSD2 wild-type (WT) cells and NSD2 KD cells