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.

中文翻译：

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肿瘤抑制因子Hic1保持染色体稳定性，独立于Tp53。

癌症中的高甲基化1（Hic1）是一种肿瘤抑制基因，通常在广泛的癌症中被表观遗传沉默和杂合丧失而失活。序列特异性锌指转录阻遏物HIC1的缺失导致以谱系特异性方式促进恶性表型的基因失调。特别是，HIC1靶基因SIRT1（组蛋白脱乙酰基酶）的上调可通过失活TP53来促进肿瘤生长。另一种证据表明，HIC1可以通过与MTA1的相互作用促进DNA双链断裂的修复，MTA1是核小体重塑和脱乙酰酶（NuRD）复合体的组成部分。现在，我们使用肿瘤切除的条件基因敲除小鼠模型显示，Hic1的失活导致细胞周期停滞，过早衰老，体外染色体不稳定性和自发转化。该表型在小鼠胚胎成纤维细胞中复制了删除Brca1（同源重组DNA修复途径的组成部分）的作用。这些作用似乎不是通过Hic1靶基因表达的失调或Tp53功能的丧失来介导的，而是支持Hic1在持续复制应激期间维持基因组完整性的作用。Hic1功能的丧失还与成年小鼠气道上皮中致癌性KRas的激活有关，导致体内形成具有微乳头表型的高度多形性腺癌。这些结果表明，在肿瘤形成的早期阶段，Hic1表达的丧失可能通过获得染色体不稳定性而促进了恶性转化。