HIC1 Suppressor Gene - Therapeutic Strategies in Cancer Biology and Pathology - page 148

promoting an inactive chromatin structure. As the name of the gene implies, the
expression of HIC1 in tumours is suppressed by methylation. Promoter methylation
of HIC1 is seen very frequently in prostate carcinoma specimens where the high fre-
quency of methylation occurred in high Gleason grade tumours (Kilinc et al., 2012).
In renal cell tumours, higher levels of methylation was found in primary tumours
which had metastasised to regional lymph nodes as compared with those which had
not metastasised (Eggers et al., 2012).
HATs and HDACs regulate gene transcription. HATs acetylate the lysine tails of his-
tones leading to an open chromatin state making genes more accessible to transcription.
But HDACs reduce histone acetylation and can suppress transcription or deregulate gene
expression. Thus modifications of histones at the post-translational level are important
regulators of gene expression (Kouzarides, 2007; Li et al., 2007b). Svedlund et al. (2012)
have argued the repressive modification of H3 histone (H3K27me2/3, i.e. di- or tri-meth-
ylation of histone H3 at lysine 27) rather than DNA methylation might be a major means
of HIC1 silencing. Deacetylation is also able to regulate HIC1 activity. HIC1 interacts
with the deacetylase SIRT1 (sirtuin 1) and this involves the last four last zinc fingers of
HIC1 and a certain defined amino acid sequence of SIRT1 (Dehennaut et al., 2012). This
sequence contains the domain called ESA (essential for SIRT1 activity) which serves as
a switch to turn on the deacetylase function (Kang et al., 2011a). This in a way confirms
that the interaction between HIC1 and SIRT1 has a functional basis.
A Resumé of Apoptosis Pathways
HIC1 is actively interacts with many pathways of apoptosis signalling. So a brief resumé
is provided here as prelude. Apoptosis can occur by the intrinsic mitochondrial pathway
where it is induced by DNA damage and other stress factors. Caspases are the major par-
ticipants of the apoptosis process. They are involved in mitochondrial as well as the death
receptor pathways. The death receptor pathway invokes the intervention of Bax/Bak/
Bcl-2, which can involve regulation by p53. This pathway constituted by TNFR (tumour
necrosis factor receptor)/TRADD (TNFR-associated death domain) or Fas receptor
(CD95) leads to the activation of caspases via FADD (Fas-associated death domain).
TRADD can function via TRAF2 (TNF-associated factor 2) towards cell survival by
NF-κB or via JNK signalling towards apoptosis (Sherbet, 2011a). This pathway would
activate apoptosis independently of p53. The intrinsic and death receptor pathways meet
downstream at the initiation of the so-called executioner caspases (caspase-3, caspase-6
and caspase-7). Apoptosis is negatively regulated by Akt, which in turn is subject to
supervision by PTEN. Many of these pathways involve HIC function together with other
interacting elements ( Figure 26.1 ) which have been discussed in some detail here.
The Alternative Reading Frame Tumour Suppressor Genes
The alternative reading frame (ARF) locus harbours the tumour suppressors, namely
p16ARF (p16 INK4a , CDKN2A) and p15ARF (p15 INK4b ). The p16ARF locus also