Page 54 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 41

has also been demonstrated to suppress the VDR responsiveness of bladder cancer
cell lines [166], notably toward the VDR ligand lithocholic acid (LCA) [193],
suggesting a role for epigenetic disruption of the capacity of cells to sense and
metabolize potential genotoxic insults.
The epigenetic lesion rising from elevated NCOR1 can be targeted by co-treat-
ment of either 1a,25(OH) D or its analogs, plus the HDAC inhibitors such as
2 3
trichostatin A, and can restore the 1a,25(OH) D -responses of androgen-indepen-
2 3
dent PC-3 cells to levels indistinguishable from control normal prostate epithelial
cells. This reversal of 1a,25(OH) D insensitivity was associated with reexpression
2 3
of gene targets associated with the control of proliferation and induction of apopto-
sis, notably GADD45A [120, 135, 185]. Similarly, targeting in breast cancer cells
through co-treatments of 1a,25(OH) D with HDAC inhibitors coordinately regu-
2 3
lated VDR targets and restored anti-proliferative responsiveness [192, 194].
Similarly, other workers have used combinatorial chemistry to combine aspects of
the structure of 1a,25(OH) D and HDAC inhibitors into a single molecule that
2 3
demonstrates very significant potency [195].
Together, these data support the concept that altered patterns of corepressors
inappropriately sustain histone deacetylation around the VDRE of specific target
gene promoter/enhancer regions, and shifts the dynamic equilibrium between apo
and holo receptor conformations, to favor transcriptional repression of key target
genes. Furthermore, targeting this epigenetic lesion with co-treatments of vitamin
D compounds plus HDAC inhibitors generates a temporal window where the equi-
3
librium point between apo and holo complexes is shifted to sustain a more tran-
scriptionally permissive environment.
These findings compliment a number of parallel studies that have established
cooperativity between 1a,25(OH) D and butyrate compounds, such as sodium
2 3
butyrate (NaB) [196–201]. These compounds are short-chain fatty acids produced
during fermentation by endogenous intestinal bacteria and have the capacity to act
as HDAC inhibitors. Stein and coworkers have identified the effects in colon cancer
cells of 1a,25(OH) D plus NaB co-treatments to include the coordinate regulation
2 3
of the VDR itself. Together these studies underscore further the importance of the
dietary-derived milieu to regulate epithelial proliferation and differentiation beyond
sites of action in the gut.

2.5 Toward an Integrated Understanding of the VDR

A highly conserved VDR is found widely throughout metazoans, even in certain
non-calcified chordates such as the lamprey (reviewed in [202]). Within prokary-
otes there appears to be the capacity to undertake UV-catalyzed metabolism of
cholesterol compounds and suggests that the evolution of vitamin D biochemistry
is very ancient. These findings suggest that the VDR system has been adapted to
regulate calcium function and retains other functions that are calcium-independent
and include the capacity to sense the local environment.