Department of Urologic Research, Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, Minnesota 55905, USA.
Decreased levels of the prostate-specific homeobox protein NKX3.1 are correlated with hormone-refractory and metastatic prostate cancer. Thus, it is compelling to define the NKX3.1-regulated genes that may be important for the progression of the advanced stage of the disease. In this study, we showed that vascular endothelial growth factor-C (VEGF-C) is one such target gene of NKX3.1. NKX3.1 inhibited VEGF-C expression in prostate cancer, and the loss of NKX3.1 led to increased VEGF-C expression. Histone deacetylase 1 acted as a corepressor of VEGF-C expression along with NKX3.1. Activated RalA acted in synergy with the loss of NKX3.1 for VEGF-C transcription. Patients with deletions at chromosome 8p21.1-p21.2 as a sole deletion developed lymph node metastasis. Interestingly, the higher expression of VEGF-C in prostate cancer is also correlated with lymph node metastasis. Therefore, regulation of VEGF-C expression by NKX3.1 provides a possible mechanism by which the loss of NKX3.1 protein level leads to lymphangiogenesis in the late stages of advanced prostate cancer.