Loss of GATA6 expression promotes lymphatic metastasis in bladder cancer

Lymph node metastasis is associated with tumor relapse and poor patient prognosis in bladder cancer. However, the mechanisms by which bladder carcinoma cells induce lymphangiogenesis and further promote metastasis in the lymphatic system remain unclear. Here, we show that the transcription factor GATA-binding factor 6 (GATA6) was substantially downregulated in bladder cancer via promoter hypermethylation. Low-level GATA6 expression significantly correlated with lymph node metastasis positivity and was able to predict earlier relapse and shorter survival of bladder cancer. Reconstitution of GATA6 inhibited lymphangiogenesis and lymph node metastasis in GATA6-low bladder cancer cells, while silencing of GATA6 rendered lymphatic metastasis in GATA6-high bladder cancer cells. Additionally, we demonstrated that GATA6 bound to the promoter of vascular endothelial growth factor (VEGF)-C, a lymphangiogenic factor, and acted as a transcriptional repressor. This GATA6/VEGF-C axis was essential for GATA6-mediated lymphatic metastasis. In bladder cancer patients, low GATA6 correlated with high VEGF-C and reduced overall survival. These findings indicate GATA6 as a pivotal regulator in the lymphatic dissemination of bladder cancer and suggest a new therapeutic target for the disease.