Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin

Peters, Antoine H.F.M.; Mermoud, Jacqueline E.; O’Carroll, Dónal; Pagani, Michaela; Schweizer, Dieter; Brockdorff, Neil; Jenuwein, Thomas

doi:10.1038/ng789

Cited by 452 publications

(335 citation statements)

References 30 publications

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“…In contrast, methylation of lysine 9 of H3 is a marker of condensed, inactive chromatin of the sort associated with the inactive X-chromosome and pericentromeric heterochromatin. [48][49][50][51] There is a report that cancer cells have increased overall levels of deacetylation of the known histone target of SIRT1, H4-K16. 52 Moreover, a recent study also suggested that global histone modification in prostate cancer, including acetylation of H3K18 and H4K12, dimethylation of H3K4 and H4R3 and acetylation of H3K9, a target of SIRT1, 53 predict a risk of prostate cancer recurrence.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

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Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-jB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: genistein; prostate cancer; tumor suppressor gene Genistein (4 0 ,5,7-trihydroxyflavone), a naturally occurring isoflavenoid abundant in soy products, has been identified as an inhibitor of protein tyrosine kinases, which play key roles in cell growth and apoptosis. 1,2 Genistein has been reported to have estrogenic properties and antineoplastic activity in multiple tumor types. 3 One mode by which hormonal agents work is by regulating gene activity by modulating epigenetic events such as histone acetylation and DNA methylation. 4,5 Genistein was also found to have epigenetic effects in the mouse prostate. 6 Taken together, these findings suggest that genistein's antitumor activity may be mediated by epigenetic-based pathways. On the other hand, genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-jB) pathway, which could be mediated via AKT (AKT8 virus oncogene cellular homolog) signaling, the most important survival pathway in cellular signaling. 7 However, the precise molecular mechanism has yet to be characterized.AKT is a serine/threonine protein kinase functioning downstream of phosphatidylinositol 3-kinase (PI3K) in response to mitogen or growth factor stimulation. High-levels of AKT activation have been associated with the development and metastasis of several cancers. 8 AKT activation not only directly inhibits apoptosis by multiple mechanisms involved in inhibiting the conformational change of Bax, BAD and caspase-9 but also modulates apoptosis indirectly by influencing the activities of several transcription factors, including fork head transcription factors (FOXO) and...

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Section: Discussionmentioning

confidence: 99%

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Kikuno

Shiina

Urakami

et al. 2008

Intl Journal of Cancer

203

149

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“…Recent studies show that methylation of histone, particularly of H3, is important to mark the inactive X; namely, H3 methylation provides an epigenetic imprint or a nucleation center for Xist RNA on the inactive X . Furthermore, the inactive X chromosome is enriched for H3 methylated at lysine 9 (H3-K9) (Boggs et al, 2002;Peters et al, 2002). It has also been demonstrated that histone methylation occurs prior to DNA methylation of CpG island (Brockdorff, 2002).…”

Section: Dna Methylation In Various Biological Phenomenamentioning

confidence: 98%

Gene silencing in phenomena related to DNA repair

Mukai

Sekiguchi²

2002

Oncogene

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DNA methylation is essential for embryonic development and important for transcriptional repression, as observed in several biological phenomena. These include genomic imprinting, X-inactivation and carcinogenesis. The basic mechanism by which DNA methlyation silences transcription is generally understood, but there is still much to be learned about how DNA methyltransferase is targeted to a specific region of the gene. Silencing by DNA methylation occurs at an early stage of carcinogenesis, when the DNA repair genes, MGMT and hMLH1, are frequently inactivated, resulting in mutations in key cancer-related genes in cells. Mice defective in Mgmt and/or Mlh1 gave clear evidence of the significant roles of these proteins in carcinogenesis.Recently, it has been demonstrated that DNA methylation is linked to histone methylation in fungi and plants, although it remains unknown whether this mechanism occurs in mammalian systems.

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“…Despite anti-H3K27me3 antibodies also recognizing H3K27me2, and anti-H3K27me2 antibodies recognizing H3K27me3, both have a clear preference for their main substrates (Peters et al, 2002). Thus, the main methylation mark on the PHE1 locus is H3K27me3.…”

Section: The Pheres1 Locus Contains H3k27 Methylation Marksmentioning

confidence: 99%

Different Polycomb group complexes regulate common target genes in Arabidopsis

et al. 2006

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Polycomb group (PcG) proteins convey epigenetic inheritance of repressed transcriptional states. Although the mechanism of the action of PcG is not completely understood, methylation of histone H3 lysine 27 (H3K27) is important in establishing PcG-mediated transcriptional repression. We show that the plant PcG target gene PHERES1 is regulated by histone trimethylation on H3K27 residues mediated by at least two different PcG complexes in plants, containing the SET domain proteins MEDEA or CURLY LEAF/SWINGER. Furthermore, we identify FUSCA3 as a potential PcG target gene and show that FUSCA3 is regulated by MEDEA and CURLY LEAF/SWINGER. We propose that different PcG complexes regulate a common set of target genes during the different stages of plant development.

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Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin

Cited by 452 publications

References 30 publications

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Gene silencing in phenomena related to DNA repair

Different Polycomb group complexes regulate common target genes in Arabidopsis

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