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

Abstract

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)

Next-Generation Sequencing Reveals Regional Differences of the α-Synuclein Methylation State Independent of Lewy Body Disease

“…Other studies also detected an increase in E2F-1 levels in the CG of PD patients compared with controls strengthening the potential implication of E2F in neuronal apoptosis (Alvira et al 2008). Sp1 is a commonly found transcription factor of CG-rich promoters (Briggs et al 1986), and E2F binds to CpGs at promoter regions with sensitivity towards DNA methylation (Jenal et al 2009). A potential role of intron 1-specific CpG methylation on transcription factor-mediated regulation of SNCA remains an open question.…”

Differential Regulation of HIC1 Target Genes by CtBP and NuRD, via an Acetylation/SUMOylation Switch, in Quiescent versus Proliferating Cells

“…E2F1 is a crucial activator of SIRT1 transcription in response to DNA damage, but SIRT1 binds and deacetylates E2F1 that inhibits E2F1-mediated gene activation (30,66). In addition, E2F1 directly activates HIC1 (27) and HIC1 directly represses the E2F1 promoter in quiescent but not in G 1 human fibroblasts, which contributes to the growth suppression induced by serum deprivation (71). Thus, HIC1 is placed at the intersection of complex regulatory loops modulating p53-dependent and E2F1-dependent cell survival, growth control, and stress responses (15).…”

Scavenger Chemokine (CXC Motif) Receptor 7 (CXCR7) Is a Direct Target Gene of HIC1 (Hypermethylated in Cancer 1)

“…In addition, SIRT1 also deacetylates HIC1 and thereby favors its SUMOylation, thus establishing optimal transcriptional repression (12). Recently, HIC1, SIRT1, and E2F1 have also been implicated in a regulatory feedback loop because HIC1 represses the E2F1 promoter (13) and because E2F1 is a transcriptional activator of HIC1 (40). Furthermore, E2F1 is a crucial activator of SIRT1 transcription in response to DNA damage, but SIRT1 binds E2F1 and deacetylates it thus inhibiting E2F1-mediated gene activation (14,15).…”