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PMID:18974119

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Citation

Zhang, H, Muders, MH, Li, J, Rinaldo, F, Tindall, DJ and Datta, K (2008) Loss of NKX3.1 favors vascular endothelial growth factor-C expression in prostate cancer. Cancer Res. 68:8770-8

Abstract

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.

Links

PubMed PMC2674365 Online version:10.1158/0008-5472.CAN-08-1912

Keywords

Base Sequence; Blotting, Western; Cell Line, Tumor; Chromatin Immunoprecipitation; DNA Primers; Gene Expression Regulation, Neoplastic/physiology; Histone Deacetylase 1; Histone Deacetylases/physiology; Homeodomain Proteins/genetics; Homeodomain Proteins/physiology; Humans; Male; Polymerase Chain Reaction; Promoter Regions, Genetic; Prostatic Neoplasms/metabolism; RNA, Messenger/genetics; RNA, Small Interfering; Transcription Factors/genetics; Transcription Factors/physiology; Vascular Endothelial Growth Factor C/genetics; Vascular Endothelial Growth Factor C/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HDAC1

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q99801

F

  • has_input:(UniProtKB:P49767)

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P49767)

Seeded From UniProt

complete

HUMAN:NKX31

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P49767)

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P49767)

Seeded From UniProt

complete

HUMAN:NKX31

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P49767)

Seeded From UniProt

complete

HUMAN:NKX31

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_input:(UniProtKB:P49767)

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P49767)

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99801

F

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q99801

F

has_input:(UniProtKB:P49767)

Seeded From UniProt

complete

See also

References

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