Epigenetic
gene silencing, associated with promoter CpG island hypermethylation, is now
recognized as one of the main mechanisms by which cancers inactivate tumour
suppressor genes. HYPERMETHYLATED IN
CANCER-1 (HIC1) is a tumour
suppressor commonly silenced by epigenetic mechanisms in cancer. Although HIC1
is a sequence-specific transcriptional repressor, its role as a tumor
suppressor is poorly understood. The most well characterized transcriptional target
of HIC1 is SIRT1, a class III histone
deactylase known to promote mammalian cell survival under oxidative stress and
DNA damage. Importantly, SIRT1 actively deactylates, and thus inactivates, P53.
We therefore hypothesized that loss of HIC1 function could substitute for p53
mutations in a cancer initiation model. To address this question, we utilized mouse
embryonic fibroblasts (MEFs) as a model for neoplastic transformation. First, we
confirmed previous reports demonstrating that MEFs with constitutive activation
of KRas (KRasG12D/+) are capable of immortalization and partial
transformation as indicated by lack of contact inhibition, but an inability to
form tumours in immuno-compromised mice.
Using a conditional Hic1 knockout
allele, we then showed that deletion of Hic1
cooperates with KRas activation to induce rapid and complete transformation in
a similar fashion to loss of p53. Remarkably, deletion of both alleles of Hic1
also resulted in complete transformation without the need for a cooperating
oncogenic stimulus. These data suggest that epigenetic silencing of HIC1 is a
potentially important alternative to P53
mutation in cancer initiation.