Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis

Abstract

The gene hypermethylated in cancer 1 (HIC1) is epigenetically inactivated, but not mutated, in cancer. Here we show that cooperative loss of Hic1 with p53, but not INK4a, yields distinct tumor phenotypes in mice. Germline deletion of one allele of each gene on the opposite chromosome yields breast and ovarian carcinomas and metastatic osteosarcomas with epigenetic inactivation of the wild-type Hic1 allele. Germline deletion of the two genes on the same chromosome results in earlier appearance and increased prevalence and aggressiveness of osteosarcomas with genetic deletion of both wild-type genes. In human osteosarcomas, hypermethylation of HIC1 is frequent only in tumors with p53 mutations. Our results indicate the importance of genes altered only through epigenetic mechanisms in cancer progression in conjunction with genetically modified tumor suppressor genes.

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

“…We hypothesize that it is neoplasia-associated events, potentially including increased proliferation and oxidative damage, which promote de novo 'type A' CpG island methylation (Issa et al, 2001). It is quite possible that epigenetic silencing of 'type A' genes ultimately promotes neoplasia (Issa et al, 1994;Ahuja et al, 1998;Chen et al, 2004;Suzuki et al, 2004), but we propose that 'type A' methylation is originally the consequence rather than the cause of carcinogenesis. Alternatively, 'type A' methylation could still be an initial but non-rate-limiting event in the CIN pathway.…”

“…DNA methylation was quantified at five 'type A' genes ESR1, GATA5, HIC1, HPP1 and SFRP1 (Issa et al, 1994;Young et al, 2001;Akiyama et al, 2003;Chen et al, 2004;Suzuki et al, 2004) and 10 'type C' markers MLH1, CDKN2A, MGMT, MINT2, MINT31, CACNA1G, IGF2, RUNX3, NEUROG1 and SOCS1 Issa, 2004;Shen et al, 2005Shen et al, , 2007bWeisenberger et al, 2006). Specific 'type A' genes were selected for their relevance to colorectal neoplasia and for evidence (unpublished data) that each had relatively high methylation within peritumoral 'normal' mucosa.…”

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

“…Indeed, HIC-1 is a gene which is methylated in many tumours without mutations (Wales et al, 1995). HIC-1 þ /À mice develop tumours with the remaining allele being methylated to inactivate the gene (Chen et al, 2004). The treatment of UCI101 with 5-azacytidine was found to cause reexpression of RPS6KA2 in this cell line as shown by RT-PCR.…”

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

“…Third, Wang et al demonstrate that heterozygous loss of SIRT1 drastically accelerates tumorigenesis in p53 þ /À background (Wang et al, 2008). Surprisingly, in the study by Wang et al, the control p53 þ /À mice develop few tumors over 20 months of observation, which is in sharp contrast to numerous studies showing that p53 þ /À mice are highly susceptible to tumorigenesis within the similar time frame (Harvey et al, 1993;Venkatachalam et al, 1998;Cressman et al, 1999;Berrigan et al, 2002;Chen et al, 2004). It is unclear if the accelerated tumorigenesis observed by Wang et al is an outcome of specific genetic background.…”