Inhibitor of DNA Binding Proteins in Tumours - Therapeutic Strategies in Cancer Biology and Pathology - page 184

with the suppressor function of the latter. The Rb protein has also been included
in the purview of ID function. IDs1-3 are shown to be often associated with pro-
motion of cell proliferation. Again as with ID4, these functions are an outcome of
activation of many signalling systems. As noted on many occasions, activation of
NF-κB signalling leads to the inhibition of apoptosis and promotion of cell popula-
tion expansion. In many cancer cell lines, ID1 has induced activation of NF-κB by
directly interacting with the p65 subunit of the NF-κB complex (Peng et al., 2012).
Investigating the expression of ID1 and p65 in NPC (nasopharyngeal carcinoma),
Sun et al. (2012) have concluded that enhanced ID1 and NF-κB/p65 correlated with
poor prognosis. They also inhibited ID1 and NF-κB/p65 using specific shRNAs in
an NPC cell line and found that the treatment had reduced MMP-9 levels and in
vitro migration of the carcinoma cells.
ID1 has been found to directly interact with the zinc finger transcription factors
EGR1 which is induced by growth factors. Exposure of neuroblastoma cell line,
SK-N-MC to FGF-2 induced ID1 expression, via activation ERK1/2 pathway and
activation of EGR1. The latter interacted with ID1 promoter and led eventually to
cell proliferation (Passiatore et al., 2011). EGR2 can function directly by inhibiting
RANKL/NF-κB and suppress apoptosis, but it can also interact with ID2 promoter
and induce its expression (Kim et al., 2012c). Some evidence has been adduced for
the participation of the TGFβ/Smad canonical pathway in ID function.
Are IDs Suitable Therapeutic Targets?
Many aspects of the function of IDs have interesting features that are exploitable
to render IDs potential targets for therapeutic management. Some efforts have been
made in this regard using conventional technology such as RNA interference to sup-
press ID genes that can promote tumour growth and spread. Many pathways of the
regulation of IDs that operate in producing changes in the growth and behaviour of
tumours have been suggested as possible targets. Elements in the regulation of apop-
totic events, such as NF-κB function, the effects on the stability of IDs from ubiq-
uitination and deubiquitination have been implicated. Certain miRNAs have been
conspicuously cited as candidates to modulate IDs, but the sheer multiplicity of the
modes of their function does not lend themselves as the most attractive elements.
Among other notable features is the promotion of angiogenesis by ID1, ID2 and ID3.
IDs may be upregulated in parallel with EGFR and VEGF but at present there is no
visible causal link. Although mechanistic studies of how IDs promote these effects
are still needed, fundamental findings are in place. Also of much significance is that
ID4 on occasions does downregulate the suppressor gene BRCA1. In general ID
expression is higher in TNBCs than non-TNBC, which could be a result of down-
regulation of the BRCA1. So in breast cancer subsets where BRCA1 is silenced,
clarification of this inverse relationship would be worthy of therapeutic pursuit. The
postulated regulatory loop consisting of ER and ID4, BRCA1 and certain MiRNAs
also holds much yet undefined promise. Inducing re-expression of ID4 by targeted
demethylation might merit some approach. We know from the work of Noetzel et al.