Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors

Chen, Wenyong; Zeng, Xiaobei; Carter, Mark G.; Morrell, Craig N.; Yen, Ray Whay Chiu; Esteller, Manel; Watkins, D. Neil; Herman, James G.; Mankowski, Joseph L.; Baylin, Stephen B.

doi:10.1038/ng1077

Cited by 189 publications

(181 citation statements)

References 20 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…This fact indicates that E2F1 induces HIC1 mRNA levels in Hep3B cells independent on the methylation status of the HIC1 P0 promoter. Importantly,hypermethylation of the P0 promoter is sufficient to silence HIC1 expression (28). In line with our methylation results, two studies measured HIC1 promoter hypermethylation in different morphologic grades of the liver and found increasing HIC1 promoter methylation from normal liver tissue, to precancerous liver tissue (showing chronic hepatitis or cirrhosis), to primary hepatocellular carcinoma, but no significant correlation between hypermethylation and HIC1 mRNA expression levels was seen (4,5).…”

Section: Discussionsupporting

confidence: 73%

The Tumor Suppressor Gene Hypermethylated in Cancer 1 Is Transcriptionally Regulated by E2F1

Jenal

Trinh²,

Britschgi³

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

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. (Mol Cancer Res 2009;7(6):916-22)

show abstract

Section: Discussionsupporting

confidence: 73%

The Tumor Suppressor Gene Hypermethylated in Cancer 1 Is Transcriptionally Regulated by E2F1

Jenal

Trinh²,

Britschgi³

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…HIC1 functions as a transcriptional repressor when deacetylated and sumoylated (Stankovic-Valentin et al, 2007). HIC1 promoter hypermethylation occurs during tumorigenesis and aging, leading to the upregulation of SIRT1 (Chen et al, 2003. The normal downregulation of SIRT1 protein seen during aging might be lost in cells without HIC1, making them resistant to replicative senescence after oxidative stress, and vulnerable to transformation if mutations are propagated.…”

Section: Regulation Of Sirt1 Expression In Primary Cells and Its Overmentioning

confidence: 99%

“…The normal downregulation of SIRT1 protein seen during aging might be lost in cells without HIC1, making them resistant to replicative senescence after oxidative stress, and vulnerable to transformation if mutations are propagated. HIC þ /À mice are tumor prone and show a p53-and SIRT1-dependent block in apoptosis induction in response to DNA damage (Chen et al, 2003. Loss of HIC1 and concomitant increase in SIRT1 prolongs lifespan, but facilitates tumor development as less apoptosis is induced in response to DNA damage.…”

Section: Regulation Of Sirt1 Expression In Primary Cells and Its Overmentioning

confidence: 99%

Sirtuins: critical regulators at the crossroads between cancer and aging

2007

View full text Add to dashboard Cite

Sirtuins (SIRTs 1À7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SIRT1, -2, -3 and -5) or ADP ribosylation (SIRT4 and -6). The orthologs of sirtuins in lower organisms play a critical role in regulating lifespan. As cancer is a disease of aging, we discuss the growing implications of the sirtuins in protecting against cancer development. Sirtuins regulate the cellular responses to stress and ensure that damaged DNA is not propagated and that mutations do not accumulate. SIRT1 also promotes replicative senescence under conditions of chronic stress. By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers. Here, we review the growing implications of sirtuins both in cancer prevention and as specific and novel cancer therapeutic targets.

show abstract

“…13,14 Hypermethylated in cancer 1 (HIC1, ZBTB29) is a member of this family and has been shown to regulate proliferation and p53-dependent survival in a wide range of tumors. HIC1 is epigenetically silenced through DNA methylation in various human cancers 15,16 and it has been proposed that HIC1-dependent repression of SIRT1 was critical for the function of p53. 17 However, the role of HIC1 in immune cells has not been examined.…”

Section: Introductionmentioning

confidence: 99%