Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells

Nkx3.1 is a homeodomain-containing transcription factor that is expressed early in the development of the prostate gland and is believed to play an important role in the differentiation of prostatic epithelia. Loss of Nkx3.1 protein expression is often an early event in prostate tumorigenesis, and the abundance of Nkx3.1 negative epithelial cells increases with disease progression. In a number of systems, homeodomain proteins collaborate with zinc-finger-containing transcription factors to bind and regulate target genes. In the present paper, we report that Nkx3.1 collaborates with Sp-family members in the regulation of PSA (prostate-specific antigen) in prostate-derived cells. Nkx3.1 forms protein complexes with Sp proteins that are dependent on their respective DNA-binding domains and an N-terminal segment of Nkx3.1, and Nkx3.1 negatively regulates Sp-mediated transcription via Trichostatin A-sensitive and -insensitive mechanisms. A distal 1000 bp portion of the PSA promoter is required for transrepression by Nkx3.1, although Nkx3.1 DNA-binding activity is itself not required. We conclude that Nkx3.1 negatively regulates Sp-mediated transcription via the tethering of histone deacetylases and/or by inhibiting the association of Sp proteins with coactivators.