Page 49 - Vitamin D and Cancer

36 J. Thorne and M.J. Campbell

activation elevates expression of p27 (kip1) , initiates cell cycle arrest, and commits
cells toward differentiation. Transcriptional control of miRNAs and their biological
effects are clearly a field of rapid expansion, and members of the NR superfamily
are implicated in their regulation [140, 141]. A role for the VDR to govern the
expression of this regulatory miRNA and, importantly, place its role in the well-
understood map of differentiation is highly novel.

2.3.2 Sensing DNA Damage

An important and emergent area, both in terms of physiology and therapeutic
exploitation, is the role the liganded VDR appears to play in maintaining genomic
integrity and facilitating DNA repair. There appears to be close cooperation
between VDR actions and the p53 tumor suppressor pathway. The maintenance of
genomic fidelity against a backdrop of self-renewal is central to the normal devel-
opment and adult function of many tissues including the mammary and prostate
glands, and the colon. For example, in the mammary gland p53 family members
play a role in gland development and maintenance. P63 -/- animals have an absence
of mammary and other epithelial structures, associated with a failure of lineage
commitment (reviewed in [142]), whereas p53 -/- animals have delayed mammary
gland involution, reflecting the Vdr -/- animals, and wider tumor susceptibility
(reviewed in [143]).
The overlap between p53 and VDR appears to extend beyond cellular pheno-
types. The VDR is a common transcriptional target of both p53 and p63 [144, 145]
and VDR and p53 share a cohort of direct target genes associated with cell cycle
arrest, signal transduction, and programmed cell death including CDKN1A
GADD45A, RB1, PCNA, Bax, IGFBP3, TGFB1/2, and EGFR [23, 128, 135, 146–
150]. At the transcriptional level, both VDR heterodimers and p53 tetramers associ-
ate, for example, with chromatin remodeling factors CBP/p300 and the SWI/SNF
to initiate transactivation [51, 151] By contrast, in the gene repressive state VDR
and p53 appear to associate with distinct repressor proteins, for example, p53 with
SnoN [152], and VDR with NCOR1, suggesting the possibly association with dis-
tinct sets of histone deacetylases. Indeed, CDKN1A promoter-dissection studies
revealed adjacent p53 and VDR-binding sites, suggesting composite responsive
regions [23]. Together, these findings suggest that 1a,25(OH) D -replete environ-
2
3
ments enhance p53 signaling to regulate mitosis negatively.
Similarly the role of 1a,25(OH) D in the skin is also suggestive of its chemo-
2
3
preventive effects. UV light from sun exposure has several effects in the skin; UVA
light induces DNA damage through increasing the level of reactive oxygen species
(ROS), but importantly UVB light also catalyzes the conversion of 7-dehydroxyc-
holesterol to 25(OH)-D and induces the expression of VDR.
In addition, antimicrobial and anti-inflammatory genes are another subset of
VDR targets that are induced by UV radiation. Suppression of the adaptive inflam-
matory response is thought to be protective for several reasons. Inflamed tissues