S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 65

(+/−)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide(OPB-9195) pre-
vented diabetic nephropathy in transgenic mice that overexpress human RAGE.
S100A4 Downregulates PRDM1 and VASH1 Suppressor Genes
The PRDM2 gene encodes two proteins, namely RIZ1 and RIZ2. PRDM2 is a
tumour suppressor gene. RIZ1 referred to here as PRDM2 is a zinc finger protein
belonging to the nuclear protein-methyltransferase superfamily. PRDM2 has a PR
domain at its N-terminus, which is absent in RIZ2. PRDM2 is capable of binding
Rb protein and ER. It is postulated to play a part in regulation of transcription of
Rb and activates ER function. The gene is located on 1p36.21, a region which is
often deleted in cancers (NCBI database). The gene is silenced by hypermethylation
in many tumours. The loss of PRDM2 shows obvious links with disease progres-
sion. In ovarian cancer decreased expression of PRDM2 has been found to corre-
late with tumour grade, clinical stage and cell proliferation (Akahira et al., 2007).
The progression of CML from the chronic phase into blast crisis occurs with par-
allel molecular changes that result in enhanced cell proliferation and survival and
arrest of differentiation. This blast crisis phenotype requires molecular alterations of
Bcr/Abl, which are deregulated in progression. These alterations affect the cell cycle
control genes, namely p53 and Rb. Lakshmikuttyamma et al. (2009) have reported
that CML progression was associated with decreased expression of PRDM2 together
with reduction in apoptosis and increase in cell proliferation.
VASH1 (vasohibin 1) inhibits cell migration, proliferation and tumour growth and
angiogenesis (Dessen and Le Minor, 2002; Watanabe et al. 2004; also see EMBL-
EBI database). Recombinant adenovirus encoding VASH1 inhibits cell proliferation
in vitro . Growth of tumours formed in vivo by subcutaneously injected H22 cells
was inhibited by VASH1. Microvessel density associated with the tumours was also
reduced, although not quantified (Li et al., 2010a). Unfortunately there is no infor-
mation about metastatic spread. However Heishi et al. (2010) found that VASH1
not only inhibited corneal vascularisation induced by VEGF-A, VEGF-C, FGF2
and PDGF-BB, but also inhibited lymhangiogenesis and spread tumours to regional
lymph nodes in a murine tumour model.
The inhibition of angiogenesis involves EZH2 (Zeste homologue 2) protein. The
EZH2 belongs to the Polycomb family. These proteins are involved in maintaining
several genes in transcriptional repression. The Polycomb group genes form two
important multi-protein complexes, namely PRC1 (Polycomb repression complex 1)
and PRC2. PRC1 is said to stably maintain gene repression, whilst PRC2 contains
HDACs and methyltransferases and initiates silencing (Kohler and Villar, 2008;
Han L et al. 2009). EZH2 is a histone-lysine N -methyltransferase PRC2 complex
and controls epigenetic modifications and so maintain genetic repression. EZH2
mediates repression of VASH1. Suppression of VASH1 by methylation upregulates
VEGF expression and promotes angiogenesis (Lu et al., 2010). Compatible with this
mode of function is the ability of S100A4 to downregulate VASH1. Suppression of