TY - JOUR
T1 - The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53
AU - Szczepny, Anette
AU - Carey, Kirstyn
AU - McKenzie, Lisa
AU - Jayasekara, W. Samantha N.
AU - Rossello, Fernando
AU - Gonzalez-Rajal, Alvaro
AU - McCaw, Andrew S.
AU - Popovski, Dean
AU - Wang, Die
AU - Sadler, Anthony J.
AU - Mahar, Annabelle
AU - Russell, Prudence A.
AU - Wright, Gavin
AU - McCloy, Rachael A.
AU - Garama, Daniel J.
AU - Gough, Daniel J.
AU - Baylin, Stephen B.
AU - Burgess, Andrew
AU - Cain, Jason E.
AU - Watkins, D. Neil
N1 - Funding Information:
Acknowledgements This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (Project Grant GNT10838550, The Victorian Cancer Agency (TS10-01), The National Institutes of Health (NCI-RO1 NS054085), The Petre Foundation, and the Victorian Government’s Operational software by a blinded observer as described [71]. Sample size was chosen based on previous studies [71]. c Representative photomicrographs of hematoxylin and eosin (H&E) stained sections of lungs from the experiment depicted in Fig. 4a. Scale bar = 5 mm. d Representative high-powered photomicrographs of hematoxylin and eosin (H&E) stained sections of lungs from the same experiment. Scale bar = 20 μm. e Representative photomicrographs of sections from the same tumors stained with immunoperoxidase (brown) for Hic1, and countersained with hematoxylin (blue). Immunohistochemistry was performed as described [71]. f Immunstaining for Proliferating cell nuclear antigen (Pcna, Dako, Troy, MI, #M087901-2) or phospho-γH2AX (γH2AX, Abcam, Cambridge, UK) in the same tumors shown in Fig. 4d. Immunohistochemistry and quantitifcation of staining was performed as described [71]. Scale bar = 100 μm. g Quantitative analysis of Pcna and γH2AX staining from the same experiment depicted in Fig. 4f. n = 5 per genotype, 5 fields of view at 40× counted per animal. **P < 0.01, unpaired t-test Infrastructure Support Program. Dr Gough is supported by an NHMRC Career Development Fellowship (GNT1063914). Dr Burgess is supported by Cancer Institute NSW Fellowship (10/FRL/3-02) and a Patricia Helen Guest Fellowship. The contents of this manuscript are solely the responsibility of the participating institutions and individual authors, and do not reflect the views of these funding agencies. We thank Dr Dominique LePrince for the gift of the Hic1-FLAG expression vector. National Health and Medical Research Council of
Funding Information:
Australia (GNT1083855): J.E.C., D.N.W.; (GNT1063914): D.J.G. National Institutes of Health (NINDS RO1 NS054085): D.N.W., S.B. B. The Petre Foundation: D.N.W. Cancer Institute of NSW Fellowship (10/FRL/ 3-02) and the Patricia Helen Guest Fellowship: A.B.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-017-0022-1
DO - 10.1038/s41388-017-0022-1
M3 - Article
C2 - 29367758
AN - SCOPUS:85040949428
SN - 0950-9232
VL - 37
SP - 1939
EP - 1948
JO - Oncogene
JF - Oncogene
IS - 14
ER -