Loss of NKX3.1 favors vascular endothelial growth factor-C expression in prostate cancer.
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.
Zhang
Heyu
H
Department of Urologic Research, Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, Minnesota 55905, USA.
Muders
Michael H
MH
Li
Jinping
J
Rinaldo
Francesca
F
Tindall
Donald J
DJ
Datta
Kaustubh
K
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases