Inhibition of lysine deacetylase activity impacts formation of the vitamin D receptor activation complex.

Abstract

The vitamin D endocrine system is responsible for the regulation of many biological processes including bone metabolism, calcium homeostasis, cell proliferation and cell differentiation. Alterations to the vitamin D signaling pathway are associated with several diseases including bone diseases, diabetes, cardiovascular diseases, autoimmune diseases, and cancer. Vitamin D precursors are obtained through diet or synthesized in the skin and must be further chemically modified to become the biologically active hormone, calcitriol. Calcitriol binds to the vitamin D receptor (VDR), a member of the nuclear hormone receptor (NHR) superfamily. VDR forms a heterodimer with retinoid X receptor (RXR) and together they bind to promoters containing vitamin D response elements (VDREs) to activate transcription of target genes. Other NHRs have been shown to accept post-translational modifications that can either increase or decrease their transcriptional output through alterations in protein-protein or protein-DNA interactions. We have generated evidence that two lysines on VDR may be targets of post-translational modifications, and alterations to lysine deacetylase activity will impact VDR transcriptional output through changes in co-activator and co-repressor binding. Together, these data suggest a novel way for the cell to modulate the response of VDR to available vitamin D.