The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1

Jenal, Mathias; Trinh, Emmanuelle; Britschgi, Christian; Britschgi, Adrian; Roh, Vincent; Vorburger, Stephan A; Tobler, Andreas; Leprince, Dominique; Fey, Martin F; Helin, Kristian; Tschan, Mario P (2009). The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1. Molecular cancer research, 7(6), pp. 916-22. Philadelphia, Pa.: American Association for Cancer Research AACR 10.1158/1541-7786.MCR-08-0359

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The Hypermethylated in Cancer 1 (HIC1) gene encodes a zinc finger transcriptional repressor that cooperates with p53 to suppress cancer development. We and others recently showed that HIC1 is a transcriptional target of p53. To identify additional transcriptional regulators of HIC1, we screened a set of transcription factors for regulation of a human HIC1 promoter reporter. We found that E2F1 strongly activates the full-length HIC1 promoter reporter. Promoter deletions and mutations identified two E2F responsive elements in the HIC1 core promoter region. Moreover, in vivo binding of E2F1 to the HIC1 promoter was shown by chromatin immunoprecipitation assays in human TIG3 fibroblasts expressing tamoxifen-activated E2F1. In agreement, activation of E2F1 in TIG3-E2F1 cells markedly increased HIC1 expression. Interestingly, expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. In conclusion, we identified HIC1 as novel E2F1 transcriptional target in DNA damage responses.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory

UniBE Contributor:

Britschgi, Christian; Vorburger, Stephan; Tobler, Andreas; Fey, Martin and Tschan, Mario

ISSN:

1541-7786

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:10

Last Modified:

04 May 2014 23:22

Publisher DOI:

10.1158/1541-7786.MCR-08-0359

PubMed ID:

19491197

Web of Science ID:

000267312500015

URI:

https://boris.unibe.ch/id/eprint/30920 (FactScience: 195282)

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