Page 44 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 31

Similarly, the ability of VDR to display transrepression, that is, ligand- dependent
transcriptional repression has received significant interest and reflects emerging
themes for other NRs, for example, PPARs [75, 76], and highlights further the
hitherto unsuspected flexibility of the VDR to associate with a diverse array of
protein factors to adapt function [77, 78]. For example, analysis of the avian PTH
gene has revealed a ligand-dependent repression of this gene by VDR [79]. The
element mediating this effect was identified as a DR3, and since it resulted in tran-
scriptional repression, the motif was referred to as a negative nVDRE. A similar
nVDRE has been identified in the human kidney in the CYP27b1 gene [80].
Interestingly, the VDR does not bind directly to this sequence; binding has been
shown to be mediated by an intermediary factor known as a bHLH-type transcrip-
tion factor, VDR interacting repressor (VDIR). It has since been shown that
liganded VDR binds to the VDIR and indirectly causes repression through HDAC
mechanisms [77].
More recently, larger and integrated responsive regions have been identified,
suggesting a yet more intricate control involving integration with other transcrip-
tion factors, for example, p53 and C/EBPa as demonstrated on the promoter/
enhancer regions of CDKN1A and SULT2A1, respectively [23, 81]. Thus, the com-
binatorial actions of the VDR with other TFs most likely go some way toward
explaining the apparent diversity of VDR biological actions. Again, for other NRs
(e.g., AR and ERa), more dominant transcription factors, so-called pioneer factors,
appear to be highly influential in determining choice and magnitude of transcrip-
tional actions [82]. Recently, C/EBP family members have been demonstrated to
act in a similar cooperative manner with the related PPARg [36] and it remains to
be established to what extent the VDR interacts similarly with other transcription
factors. The above findings are suggestive of a similar mechanism.
Efforts to understand VDR function have at their basis the antagonism between
these apo and holo receptor complexes and the ability of these complexes to sense
and regulate a diverse range of histone modifications. Histone modifications at the
level of meta-chromatin architecture appear to form a stable and heritable “histone
code,” such as in X chromosome inactivation (reviewed in [83]). The extent to
which similar processes operate to govern the activity of micro-chromatin contexts,
such as gene promoter regions, is an area of debate [84, 85]. The apo and holo NR
complexes initiate specific and coordinated histone modifications [86, 87] to gov-
ern transcriptional responsiveness of the promoter. There is good evidence that
specific histone modifications also determine the assembly of transcription factors
on the promoter, and control individual promoter transcriptional responsiveness
[88–90]. It is less clear to what extent complexes containing NRs in general, and
VDR specifically, recognize basal histone modifications on target gene promoters;
functional studies of the SANT motif contained in the corepressor NCoR2/SMRT
support this latter idea [91]. This is a complex and rapidly evolving area and the
reader is referred to an excellent recent review [75].
Collectively, these findings support the concept that the VDRs transcriptional
actions reflect a convergence of multiple complexes, the details of which are still
emerging and reflect the cross-talk, both cooperatively and antagonistically