Page 26 - Vitamin D and Cancer

1 Vitamin D: Synthesis and Catabolism 13

suggested that in poorly differentiated cancerous lesions, regions of the CYP24A1
promoter were demethylated and those of CYP27B1 were methylated (Khorchide
et al., manuscript in preparation).
In prostate cells, Khorchide et al. [95] demonstrated that human normal prostate
cells possess CYP27B1 expression, but are devoid of CYP24A1, whereas DU-145
prostate cancer cells display high CYP24A1 and very low CYP27B1 mRNA
expression. Treatment with the methylation inhibitor 5-aza-2¢-deoxycytidine
together with the histone deacetylation (HDAC) inhibitor trichostatin A, elevated
both CYP27B1 as well as CYP24A1 mRNA expression in the normal cell line. In
DU-145 cells, 5-aza-2¢-deoxycytidine plus trichostatin A elevated CYP27B1
mRNA and, importantly, also its activity as measured by HPLC [95]. Another
HDAC inhibitor, SAHA, induced CYP27B1 mRNA expression in prostate cells as
well, however at the high dose of 15 mM only [96]. In contrast, Banwell et al. were
able to demonstrate that vitamin D-insensitive prostate and breast cells when
treated with 1,25-(OH) D together with nanomolar doses of HDAC inhibitors,
2 3
were growth-inhibited synergistically. They suggest that insensitivity to vitamin D
could be due to epigenetic mechanisms involving the VDR [97].

1.3 Regulation of CYP27B1 and of CYP24A1 Expression
by Nutrition

The colorectum, as part of the digestive system, clearly is particularly affected by
nutritional components. Therefore, this section will address nutrient regulation of
vitamin D hydroxylases primarily in colorectal malignancies. However, there is
some indication that also prostate as well as mammary cancer cells might be
affected, though mechanistic evidence for this is more difficult to obtain.
It is clear that, for prevention of sporadic malignancies, average 25-(OH)D
3
levels at or above at least 40 nM need to be achieved in the general population,
though there is still some discussion about the exact amount. However, optimiza-
tion of extrarenal production of 1,25-(OH) D is essential as well. Experimental
2 3
proof is accumulating that nutrient factors such as calcium, phytoestrogens, and
folate could regulate expression of vitamin D hydroxylases.

1.3.1 Regulation of Vitamin D Metabolism in the Gut
Mucosa by Calcium

It is intriguing that vitamin D in combination with high intake of calcium from
dietary sources or supplements, apparently is much more effective in reducing the
risk of colorectal cancer than when given alone [98–100]. To investigate this
further, we availed ourselves of a mouse model. Feeding male and female mice
an AIN76 minimal diet containing 0.04% calcium led to enhanced positivity for