Aberrant Nuclear Export of circNCOR1 Underlies SMAD7-Mediated Lymph Node Metastasis of Bladder Cancer

Circular RNAs (circRNA) containing retained introns are normally sequestered in the nucleus. Dysregulation of cellular homeostasis can drive their nuclear export, which may be involved in cancer metastasis. However, the mechanism underlying circRNA nuclear export and its role in lymph node (LN) metastasis of bladder cancer remain unclear. Here, we identify an intron-retained circRNA, circNCOR1, that is significantly downregulated in LN metastatic bladder cancer and is negatively associated with poor prognosis of patients. Overexpression of circNCOR1 inhibited lymphangiogenesis and LN metastasis of bladder cancer in vitro and in vivo. Nuclear circNCOR1 epigenetically promoted SMAD7 transcription by increasing heterogeneous nuclear ribonucleoprotein L (hnRNPL)-induced H3K9 acetylation in the SMAD7 promoter, leading to inhibition of the TGF(3-SMAD signaling pathway. Nuclear retention of circNCOR1 was regulated by small ubiquitinlike modifier (SUMO)ylation of DDX39B, an essential regulatory factor responsible for circRNA nuclear-cytoplasmic transport. circNCOR1 retention in the nucleus to suppress bladder cancer ar export of circNCOR1, impairing the suppressive role of circNCOR1 on TGF(3-SMAD cascade activation and bladder cancer expression of circNCOR1 and inhibition of TGF(3 signaling significantly repressed tumor growth and LN metastasis. This study highlights SUMOylation-induced nuclear export of circNCOR1 as a key event regulating TGF(3-SMAD signaling and bladder cancer lymphangiogenesis, thus supporting circNCOR1 as a novel thera-peutic agent for patients with LN metastatic bladder cancer.