HIC1 Suppressor Gene - Therapeutic Strategies in Cancer Biology and Pathology - page 152

HIC1 is a Downstream Target of p53
HIC1 targets several genes. Of these some may be directly relevant to the biologi-
cal processes associated with cell proliferation, apoptosis and transformation. Many
investigations have focused on the regulation of apoptosis by HIC1. Wales et al.
(1995) not only identified HIC1 as a tumour suppressor gene possessing as a con-
sensus p53 binding site in the 5′ flanking region 4 kB upstream of its transcription
site of the gene and also that it is activated by wild-type p53. This was a finding of
enormous significance since p53 is mutated in a majority of human cancers leading
to a loss of its cell cycle regulatory function. But transfection of HIC1 showed that it
can suppress growth independently of the wild-type or mutant status of the recipient
cells, thus not to the exclusion of other pathways.
HIC1 Can Function Independently of p53
CtBPs have been strongly implicated in promoting EMT and tumour progression,
inhibition of tumour suppressor genes and suppression of apoptosis. The two splice
variants of CtBP1 and CtBP2 are widely expressed in tumour tissues and cell lines.
It has been reported that the downregulation of CtBPs inhibits tumour cell invasion
and promotes apoptosis independently of p53. This is possibly due to transcrip-
tional repression of p21 waf1 , a downstream target of p53 by CtBP. CtBP is able to
inhibit the transactivation of the p21 promoter by BRCA1. The integrity of BRCA1
C-terminal repeats is essential for BRCA1 to transactivate the p21 promoter, which
suggests that these repeats bind to CtBP to regulate the transcription of p21 (Li et al.,
1999). PARP1 also influences p21 expression, but this also requires CtBP (Madison
and Lundblad, 2010). With these different modes of functional interaction, it would
be needless to reiterate the ability of HIC1 to act independently of p53.