Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses.
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.
Chen
Wen Yong
WY
Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland 21231, USA.
Wang
David H
DH
Yen
Raywhay Chiu
RC
Luo
Jianyuan
J
Gu
Wei
W
Baylin
Stephen B
SB
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D044127:Epigenesis, Genetic; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012513:Sarcoma, Experimental / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D012983:Soft Tissue Neoplasms / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins