Page 48 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 35

2.3.1 Cell Cycle Arrest

A common anti-proliferative VDR function is associated with arrest at G /G of the
1
0
cell cycle, coupled with upregulation of a number of cell cycle inhibitors including
p21 (waf1/cip1) and p27 (kip1) . Promoter characterization studies have demonstrated a
series of VDREs in the promoter/enhancer region of CDKN1A [23, 129]. By con-
trast, the regulation of the related CDKI p27 (kip1) is mechanistically enigmatic,
reflecting both transcriptional and translational regulation such as enhanced mRNA
translation, and attenuating degradative mechanisms [130–133].
The up-regulation of p21 (waf1/cip1) and p27 (kip1) principally mediate G cell cycle
1
arrest, but 1a,25(OH) D has been shown to mediate a G /M cell cycle arrest in a
3
2
2
number of cancer cell lines via direct induction of GADD45a [127, 134, 135].
Again, this regulation appears to combine direct gene transcription and a range of
posttranscriptional mechanisms. These studies highlight the difficulty of establish-
ing strict transcriptional effects of the VDR, as a range of posttranscriptional effects
act in concert to regulate target protein levels. Concomitant with changes in the cell
cycle there is some evidence that 1a,25(OH) D also induces differentiation, most
2
3
clearly evidenced in myeloid cell lines, but also supported by other cell types and
most likely reflects the intimate links that exist between the regulation of the G
1
transition, the expression of CDKIs such as p21 (waf1/cip1) , and the induction of cellular
differentiation [136].
Historically, hematological malignancies combined an ease of interrogation with
robust classification of cellular differentiation capacity which was envied by inves-
tigators of solid tumors. It is therefore no coincidence that these cell systems
yielded many important insights for cancer cell biologists generally, such as chro-
mosomal translocations and instability, and the role of committed adult stem cells.
Indeed, the capacity to readily differentiate in response to external and internal
signals has fascinated leukemia researchers as they have sought to understand why
leukemia cells appear to fail at certain stages of differentiation. It is within this
context that in the 1980s, investigators [137, 138] considered a role for the VDR
and the related retinoic acid receptor (RAR) to reactivate dormant differentiation
programs in so-called differentiation therapies. Over the following 2 decades,
researchers began to reveal how these receptors instill mitotic restraint and facilitate
differentiation programs and how discord over the control and integration of these
processes is central to leukemogenesis. Despite these efforts, clinical exploitation
of these receptors has largely proved to be equivocal. The one exception to this
translational failure has been the exploitation of RAR signaling in patients with
acute promyelocytic leukemia. Again, understanding the basic signaling behind this
application proved significant to the developing understanding of epigenetic regula-
tion of transcription and the promise of HDAC inhibitors [139].
Against this backdrop, various groups, including that of Studzinski, have worked
consistently exploring mechanisms of resistance to VDR signaling and methods of
exploitation and recently demonstrated, elegantly, a role for VDR to down-regulate
miR181a, which when left unchecked degrades p27 (kip1) . Thus, indirectly VDR