Suppressor Function of NDRG1 - Therapeutic Strategies in Cancer Biology and Pathology - page 96

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Suppressor Function of NDRG1

The NDRG1 (also known as of Cap43 and Drg-1) gene, as the name implies, is reg-
ulated, indeed suppressed, by N-myc gene. This is one of possibly a four member
family of genes, NDRG1, -2, -3 and -4. Some of them show organ/tissue-specific
distribution (Zhou et al., 2001) and possibly subserve different biological functions.
NDRG4 which is expressed almost exclusively in the heart and brain may be essen-
tial for the survival of primary astrocytes and might indeed support the viability of
components of glioblastoma multiforme (Schilling et al., 2009). The NDRGs may be
involved in the pathogenesis of many human conditions. NDRG1 was identified and
originally described as a stress-regulated and hypoxia-inducible and possibly a dif-
ferentiation-related gene and has been attributed putatively with tumour and metasta-
sis function. It is downregulated in many forms of cancer. Loss of expression of the
gene has inversely correlated with tumour invasion, nodal dissemination and gener-
ally predictive of poor prognosis. Silencing of the gene has been linked with histone
acetylation rather than with hyper-methylation of the promoter (Li and Chen, 2011).
Equally, NDRG1 may be upregulated even in tumours on account of the prevailing
hypoxic environment.
NDRG1 is able to inhibit tumour growth and cell migration, both essential bio-
logical elements of metastatic spread. The NDRG1 suppressor signals appear to
be activated by many ligands and transduced through signalling channels such as
the p53, NO and Wnt signalling cascades. Aberrant Wnt/β-catenin signalling is an
important aspect of promotion of metastasis and discussed in an earlier context. The
Wnt pathway is effectively inhibited by NDRG1. NDRG1 also inhibits ATF3 which
supports metastasis, and Wnt/β-catenin/TCF signalling has been implicated in this
process (Liu et al., 2012d). ATF3 is a stress-inducible transcriptional repressor. The
stress response is mediated by the JNK/MAPK or p53-dependent signalling pathway.
The p53 gene can induce transcription of ATF3. The myc gene in contrast inhibits
NDRG1 but can activate ATF3. A new dimension added to the signalling picture is
that EMT induced by TGF-β is inhibited by the upregulation of NDRG1 in HT-29
and DU145 cells by iron chelators. They also appear to preserve E-cadherin and
β-catenin at the cell membrane, also thus implicating Wnt signalling (Chen et al.,
2012b). In prostate cancer, reduced expression of membrane-associated NDRG1
closely corresponded with reduced expression of E-cadherin and the loss of both
these correlated with poor prognosis (Song et al., 2010b). Thus one can envisage a
complex regulatory cycle involving NDRG1, p53, myc, TGF-β and Wnt/β-catenin
signalling together with ATF3 participation in the inhibition of EMT as well the met-
astatic process ( Figure 15.1 ).