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PMID:16269335

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Citation

Chen, WY, Wang, DH, Yen, RC, Luo, J, Gu, W and Baylin, SB (2005) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123:437-48

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.

Links

PubMed Online version:10.1016/j.cell.2005.08.011

Keywords

Adenocarcinoma/metabolism; Adenocarcinoma/pathology; Aging/physiology; Animals; Apoptosis/drug effects; Apoptosis/physiology; Cell Line; Cell Line, Tumor; Cercopithecus aethiops; DNA Damage/drug effects; DNA Damage/physiology; Epigenesis, Genetic; Humans; Kruppel-Like Transcription Factors; Lung Neoplasms/metabolism; Lung Neoplasms/pathology; Lymphoma/metabolism; Lymphoma/pathology; Methylation; Mice; Promoter Regions, Genetic; Protein Binding; Protein Structure, Tertiary; Sarcoma, Experimental/metabolism; Sarcoma, Experimental/pathology; Sirtuin 1; Sirtuins/genetics; Sirtuins/metabolism; Soft Tissue Neoplasms/metabolism; Soft Tissue Neoplasms/pathology; Transcription Factors/genetics; Transcription Factors/metabolism; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HIC1

involved_in

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIR1

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SIR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9R1Y5

F

Seeded From UniProt

complete

MOUSE:HIC1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HIC1

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HIC1

involved_in

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HIC1

involved_in

GO:0043517: positive regulation of DNA damage response, signal transduction by p53 class mediator

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HIC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q923E4

F

Seeded From UniProt

complete

MOUSE:SIRT1

involved_in

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SIRT1

part_of

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SIR1

part_of

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SIR1

involved_in

GO:0008630: intrinsic apoptotic signaling pathway in response to DNA damage

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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