SUMOylation-driven mRNA circularization enhances translation and promotes lymphatic metastasis of bladder cancer.

Aberrant gene expression is a prominent feature of metastatic cancer. Translational initiation is a vital step in fine-tuning gene expression. Thus, exploring translation initiation regulators may identify therapeutic targets for preventing and treating metastasis. Herein, we identified that DHCR24 was overexpressed in lymph node (LN) metastatic bladder cancer (BCa) and correlated with poor prognosis of patients. DHCR24 promoted lymphangiogenesis and LN metastasis of BCa in vitro and in vivo. Mechanistically, DHCR24 mediated and recognized the SUMO2 modification at lysine 108 of hnRNPA2B1 to foster TBK1 mRNA circularization and eIF4F initiation complex assembly by enhancing hnRNPA2B1-eIF4G1 interaction. Moreover, DHCR24 directly anchored to TBK1 mRNA 3'-untranslated region to increase its stability, thus forming a feedforward loop to elevate TBK1 expression. TBK1 activated PI3K/Akt signaling to promote VEGF-C secretion, resulting in lymphangiogenesis and LN metastasis. DHCR24 silencing significantly impeded BCa lymphangiogenesis and lymphatic metastasis in a patient-derived xenograft model. Collectively, these findings elucidate DHCR24-mediated translation machinery that promotes lymphatic metastasis of BCa and support the potential application of DHCR24-targeted therapy for LN-metastatic BCa.