Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses

Yong Chen Wen, David H. Wang, Chiu Yen RayWhay, Jianyuan Luo, Wei Gu, Stephen B. Baylin

Research output: Contribution to journalArticle

460 Citations (Scopus)

Abstract

Hypermethylated in cancer 1 (HIC1) is an epigenetically regulated transcriptional repressor that functionally cooperates with p53 to suppress age-dependent development of cancer in mice. Here we show that the mechanism by which the loss of HIC1 function promotes tumorigenesis is via activating the stress-controlling protein SIRT1 and thereby attenuating p53 function. HIC1 forms a transcriptional repression complex with SIRT1 deacetylase, and this complex directly binds the SIRT1 promoter and represses its transcription. Inactivation of HIC1 results in upregulated SIRT1 expression in normal or cancer cells; this deacetylates and inactivates p53, allowing cells to bypass apoptosis and survive DNA damage. Inhibition of SIRT1 function in cells without HIC1 abolishes the resistance to apoptosis. Since aging increases promoter hypermethylation and epigenetic silencing of HIC1, we speculate that the resultant upregulation of SIRT1 may be a double-edged sword that both promotes survival of aging cells and increases cancer risk in mammals.

Original languageEnglish (US)
Pages (from-to)437-448
Number of pages12
JournalCell
Volume123
Issue number3
DOIs
StatePublished - Nov 4 2005

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DNA Damage
Tumors
DNA
Aging of materials
Cells
Apoptosis
Neoplasms
Mammals
Transcription
Proteins
Cell Aging
Heat-Shock Proteins
Epigenomics
Cell Survival
Carcinogenesis
Up-Regulation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. / Wen, Yong Chen; Wang, David H.; RayWhay, Chiu Yen; Luo, Jianyuan; Gu, Wei; Baylin, Stephen B.

In: Cell, Vol. 123, No. 3, 04.11.2005, p. 437-448.

Research output: Contribution to journalArticle

Wen, Yong Chen ; Wang, David H. ; RayWhay, Chiu Yen ; Luo, Jianyuan ; Gu, Wei ; Baylin, Stephen B. / Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. In: Cell. 2005 ; Vol. 123, No. 3. pp. 437-448.
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