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Oncogene. 2018 Apr;37(14):1939-1948. doi: 10.1038/s41388-017-0022-1. Epub 2018 Jan 25.

The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53.

Author information

1
Centre for Cancer Research, Hudson Institute for Medical Research, Clayton, VIC, Australia.
2
Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
3
Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
4
Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
5
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
6
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
7
Department of Pathology, St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia.
8
Department of Surgery, St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia.
9
The Sidney Kimmel Cancer Centre at Johns Hopkins, Baltimore, MD, USA.
10
Centre for Cancer Research, Hudson Institute for Medical Research, Clayton, VIC, Australia. jason.cain@hudson.org.au.
11
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. n.watkins@garvan.org.au.
12
St Vincent's Clinical School, UNSW Faculty of Medicine, Sydney, NSW, Australia. n.watkins@garvan.org.au.
13
Department of Thoracic Medicine, St Vincent's Hospital, Sydney, NSW, Australia. n.watkins@garvan.org.au.

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.

PMID:
29367758
PMCID:
PMC5886987
DOI:
10.1038/s41388-017-0022-1
[Indexed for MEDLINE]
Free PMC Article

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