The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53

Abstract

Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of-heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex. Using a conditional knockout mouse model of tumor initiation, we now show that inactivation of Hic1 results in cell cycle arrest, premature senescence, chromosomal instability and spontaneous transformation in vitro. This phenocopies the effects of deleting Brca1, a component of the homologous recombination DNA repair pathway, in mouse embryonic fibroblasts. These effects did not appear to be mediated by deregulation of Hic1 target gene expression or loss of Tp53 function, and rather support a role for Hic1 in maintaining genome integrity during sustained replicative stress. Loss of Hic1 function also cooperated with activation of oncogenic KRas in the adult airway epithelium of mice, resulting in the formation of highly pleomorphic adenocarcinomas with a micropapillary phenotype in vivo. These results suggest that loss of Hic1 expression in the early stages of tumor formation may contribute to malignant transformation through the acquisition of chromosomal instability.

HIC1 deletion promotes breast cancer progression by activating tumor cell/fibroblast crosstalk

“…Here, we showed that conditional deletion of HIC1 in the mouse mammary gland may contribute to premalignant transformation at the early stage of tumor formation, inducing the formation of hyperplastic epithelium and increased expression of the proliferative markers Ki67 and cyclin D1 in mammary gland. Mechanistically, loss of HIC1 expression in lung cancer contributes to malignant transformation through the acquisition of chromosomal instability (38), which suggests that it may also correlate with mammary gland tumorigenesis. Furthermore, it has been reported that HIC1 acts as a nuclear modulator of the Wnt-signaling pathway by recruiting TCF4 and β-catenin to HIC1 bodies to exert its suppression functions (39).…”

Expression of the miR-302/367 microRNA cluster is regulated by a conserved long non-coding host gene

“…Hyper methylated In Cancer 1 (HIC1) is a transcriptional repressor that acts as a tumor suppressor and frequently is inactivated by epigenetic silencing. It has been shown to negatively regulate the WNT signaling pathway [44,45]. Growth Factor Independence 1 (GFI1) is a zinc finger protein, which acts as a transcriptional repressor.…”

Opposite Roles of the JMJD1A Interaction Partners MDFI and MDFIC in Colorectal Cancer

“…Mechanistically, HIC1 was shown to repress the SIRT1 gene promoter, thereby preventing SIRT1-mediated deacetylation and inactivation of the tumor suppressor TP53 38 . However, another way how HIC1 can suppress tumorigenesis independent of TP53 is through averting chromosomal instability 39 . Therefore, it is tempting to hypothesize that MDFIC also regulates TP53 activity and genome integrity.…”