Silent science | Nature Reviews Cancer

Access through your institution Buy or subscribe Hypermethylated in cancer 1 (HIC1) is an epigenetically regulated transcriptional repressor that cooperates with p53 to prevent the

development of cancer in ageing mice. However, how HIC1 functions as a tumour suppressor has been unclear. Given that p53 transactivates HIC1 expression in cancer cells, the authors have

previously suggested that HIC1 might be involved in a feedback loop to regulate p53 function. To examine this hypothesis, the authors examined p53 function in _Hic1_-null mouse embryonic

fibroblasts (MEFs) and confirmed that these MEFs are more resistant to the DNA-damaging agent etoposide. Conversely, the re-expression of HIC1 in MCF7 cells, in which HIC1 is silenced

because of promoter hypermethylation, increased the sensitivity of these cells to etoposide compared with controls. So, how might HIC1 regulate p53-mediated DNA-damage control? HIC1 has an

N-terminal poxvirus and zinc finger (POZ) domain that enables its interaction with a type III histone deacetylase (HDAC), inferred by the resistance of this complex to the HDAC inhibitor

trichostatin A (TSA). Moreover, the TSA-resistant HDAC, SIRT1, is known to regulate p53. The authors demonstrated a direct interaction between HIC1 and SIRT1, mediated by the HIC1 POZ

domain. Furthermore, they found that HIC1 directly regulates SIRT1 expression — levels of SIRT1 expression are increased in _Hic1_-null MEFs, and chromatin immunoprecipitation (ChIP) on ChIP

assays demonstrated that SIRT1 and HIC1 form a stable repression complex on the _SIRT1_ promoter. This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support ORIGINAL RESEARCH PAPER * Chen, W. Y. et al. Tumour suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent

DNA-damage responses. _Cell_ 123, 437–448 (2005) Article  CAS  Google Scholar  Download references Authors * Nicola McCarthy View author publications You can also search for this author

inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE McCarthy, N. Silent science. _Nat Rev Cancer_ 5, 919 (2005).

https://doi.org/10.1038/nrc1772 Download citation * Issue Date: 01 December 2005 * DOI: https://doi.org/10.1038/nrc1772 SHARE THIS ARTICLE Anyone you share the following link with will be

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