Inhibitor of DNA Binding Proteins in Tumours - Therapeutic Strategies in Cancer Biology and Pathology - page 178

In colorectal cancer, no methylation was detected in normal epithelia and adeno-
mas, but primary carcinomas and liver metastases showed hypermethylation in 49/92
and 19/26 cases, respectively (Umetani et al., 2004). Thus, to date the indications
are that hypermethylation of the gene seems to reflect tumour progression. However,
methylation status of colon cancer did not correlate with prognosis (Tanaka et al.,
2011). But Vinarskaja et al. (2012) have added a note of caution in assessing the
degree of methylation. For, they found methylation-specific PCR and pyrosequenc-
ing techniques were not always consistent with each other. The degree of gene
silencing might relate to the gene copies methylated or the degree of methylation
(Matzke et al., 1994). But one cannot be certain or assume that the degree of meth-
ylation relates pro rata to gene silencing.
Cdc42 has recently been ascribed a role in the methylation of ID4. The latter was
found to be downregulated by Cdc42, which is overexpressed in a majority of colo-
rectal adenocarcinomas (Del Pulgar et al., 2008). The mechanism involved has not
been elucidated. However, the implications of this in terms of accentuating the effects
of loss of ID4 suppressor function can be visualised immediately because Cdc42 is a
Rho-GTPase which transduces signals arising from the activation of a variety of mem-
brane receptors into induction of apoptosis, regulation of the cell cycle, modulation of
cytoskeletal organisation leading to cell migration ( Figure 30.1 ).
As discussed earlier, DLC1 possesses a Rho-GAP domain and GAP activity spe-
cific for small GTPases RhoA and Cdc42. The suppressor function of DLCs is said
to derive from their Rho-GAP activity negatively regulating RhoA, RhoB, RhoC
and to a limited extent Cdc42. The KAI1 suppressor gene might selectively inhibit
Rho-GTPases/Rho/Rac/cdc42 signalling cell motility and also modulate signalling

GPCR Growth factors Integrins

Cdc42

miRNAs ID4

DLC1

MAPK signalling
P38//ERK//JNK

KAI1

PAK1

Cytoskeletal
dynamics

Stress
response

rowth/differentiationCellpolarity/i nvasion

apoptosis ellcycle regulation

Figure 30.1 The Cdc42/Rho-GTPases/Rho/Rac signalling pathway regulating apoptosis, cell
cycle regulation, growth differentiation and cell invasion. The operation of this pathway is
modulated by some miRNAs and the suppressor genes DLC1 and KAI1. It would be worth
mentioning here that ID4 aids the development of the mammary gland by suppressing MAPK/p38
activity, but this signalling is active in ID4−/− cells (Dong et al., 2011).