HIC1 Suppressor Gene - Therapeutic Strategies in Cancer Biology and Pathology - page 147

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HIC1 Suppressor Gene

HIC1 is a tumour suppressor whose expression is suppressed in a wide variety of
cancers. The gene encodes a transcriptional repressor with five Krüppel-like C2H2
zinc fingers that facilitate sequence-specific DNA binding and two repressor
domains, viz. an N-terminal BTB/POZ (broad complex Tramtrack bric-a-brac/Pox
virus and zinc-finger) domain that is characteristic of transcriptional regulators and a
central region which engages different co-repressors, e.g. the CtBP (C-terminal EIA
binding protein) and NuRD complexes (Deltour et al., 2002; Fleuriel et al., 2009;
Pinte et al., 2004; Wales et al, 1995). CtBPs have been strongly implicated in pro-
moting EMT and tumour progression, inhibition of tumour suppressor genes, and
suppression of apoptosis (Chinnaddurai, 2009). The NuRD complex has histone dea-
cetylases, histone binding proteins and Mi-2-like proteins and the tumour promoter
gene MTA (see discussion about MTA on pp. 77-79).
It has emerged from the recent work that the BTB/POZ (broad complex
Tramtrack bric-a-brac/Pox virus and zinc-finger) domain of HIC1 recruits PCR
(Polycomb repression complex) 2 (Boulay et al., 2012). The Polycomb group genes
form two important multi-protein complexes, namely PRC1 and PRC2. PRC1 is
said to stably maintain gene repression, whilst PRC2 contains HDACs and meth-
yltransferses EZH1 or EZH2 (enhancer of Zeste homologue 2), SUZ12, and initi-
ates silencing (Han et al., 2009; Kohler and Villar, 2008). EZH2 is a histone-lysine
N -methyltransferase which catalyses H3K27me2/3, that is di- or tri-methylation of
histone H3 at lysine 27 and with these epigenetic modifications maintain genetic
repression. The molecular structure of HIC1 does suggest potentially significant
links with the regulation of cell proliferation and growth control, cell survival and
DNA damage response and tumorigenesis.

Silencing of HIC1 in Tumours

Gene silencing occurs by one of four mechanisms, namely methylation of the
gene promoter, histone deacetylation, histone methylation and ubiquitination. The
arginine and lysine residues of histones are the main targets of methylation; his-
tone methylation can repress or activate transcription. Ubiquitination of histones is
another mode of regulation of transcription. Ubiquitination of the core histone H2A
frequently leads to gene silencing whilst H2B ubiqutination leads to activation.
The methylation of cytosine bases in the DNA can prevent the binding of tran-
scription factors to gene promoters or facilitate the engagement of transcrip-
tion repressors to methylated DNA. Also methylation can repress transcription by