Home LiteratureArticle Details
PMID: 18701507 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Role of hMOF-dependent histone H4 lysine 16 acetylation in the maintenance of TMS1/ASC gene activity.

Cancer research ·Vol. 68 ·No. 16 ·2008-08-15 ·Pages 6810-21

Kapoor-Vazirani P, Kagey JD, Powell DR, Vertino PM

Abstract

Epigenetic silencing of tumor suppressor genes in human cancers is associated with aberrant methylation of promoter region CpG islands and local alterations in histone modifications. However, the mechanisms that drive these events remain unclear. Here, we establish an important role for histone H4 lysine 16 acetylation (H4K16Ac) and the histone acetyltransferase hMOF in the regulation of TMS1/ASC, a proapoptotic gene that undergoes epigenetic silencing in human cancers. In the unmethylated and active state, the TMS1 CpG island is spanned by positioned nucleosomes and marked by histone H3K4 methylation. H4K16Ac was uniquely localized to two sharp peaks that flanked the unmethylated CpG island and corresponded to strongly positioned nucleosomes. Aberrant methylation and silencing of TMS1 was accompanied by loss of the H4K16Ac peaks, loss of nucleosome positioning, hypomethylation of H3K4, and hypermethylation of H3K9. In addition, a single peak of histone H4 lysine 20 trimethylation was observed near the transcription start site. Down-regulation of hMOF or another component of the MSL complex resulted in a gene-specific decrease in H4K16Ac, loss of nucleosome positioning, and silencing of TMS1. Gene silencing induced by H4K16 deacetylation occurred independently of changes in histone methylation and DNA methylation and was reversed on hMOF reexpression. These results indicate that the selective marking of nucleosomes flanking the CpG island by hMOF is required to maintain TMS1 gene activity and suggest that the loss of H4K16Ac, mobilization of nucleosomes, and transcriptional down-regulation may be important events in the epigenetic silencing of certain tumor suppressor genes in cancer.

MeSH Terms
Acetylation Antigens, CD Apoptosis/physiology Blotting, Western Breast Neoplasms/genetics,metabolism,pathology CARD Signaling Adaptor Proteins Cadherins/genetics,metabolism Cells, Cultured Chromatin Immunoprecipitation CpG Islands Cytoskeletal Proteins/genetics,metabolism Epigenesis, Genetic Estrogen Receptor alpha/genetics,metabolism Fibroblasts/metabolism,pathology Gene Expression Regulation, Neoplastic Histone Acetyltransferases/physiology Histones/physiology Humans Kidney/metabolism,pathology Lysine/chemistry Methylation Nucleosomes/physiology Polymerase Chain Reaction RNA, Small Interfering/pharmacology
Chemicals
Antigens, CD CARD Signaling Adaptor Proteins CDH1 protein, human Cadherins Cytoskeletal Proteins ESR1 protein, human Estrogen Receptor alpha Histones Nucleosomes PYCARD protein, human RNA, Small Interfering Histone Acetyltransferases KAT8 protein, human Lysine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kapoor-Vazirani Priya
Department of Radiation Oncology and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Kagey Jacob D
Powell Doris R
Vertino Paula M
References (50)
50 references, click to expand
  1. Modulation of ISWI function by site-specific histone acetylation.
    EMBO Rep. 2002 Mar;3(3):242-7 PMID: 11882543
  2. Aberrant methylation and down-regulation of TMS1/ASC in human glioblastoma.
    Am J Pathol. 2004 Oct;165(4):1151-61 PMID: 15466382
  3. The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma.
    Int J Cancer. 2008 Mar 15;122(6):1207-13 PMID: 18058815
  4. ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway.
    Nat Cell Biol. 2004 Feb;6(2):121-8 PMID: 14730312
  5. Cancer epigenetics.
    Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R65-76 PMID: 15809275
  6. Genome-scale identification of nucleosome positions in S. cerevisiae.
    Science. 2005 Jul 22;309(5734):626-30 PMID: 15961632
  7. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine.
    Cancer Res. 2002 Nov 15;62(22):6456-61 PMID: 12438235
  8. Distinctive patterns of histone H4 acetylation are associated with defined sequence elements within both heterochromatic and euchromatic regions of the human genome.
    Nucleic Acids Res. 1998 Feb 15;26(4):994-1001 PMID: 9461459
  9. Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells.
    Cancer Res. 1994 May 15;54(10):2552-5 PMID: 8168078
  10. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.
    Nat Genet. 2007 Apr;39(4):457-66 PMID: 17334365
  11. Constitutive nucleosome depletion and ordered factor assembly at the GRP78 promoter revealed by single molecule footprinting.
    PLoS Genet. 2006 Sep 22;2(9):e160 PMID: 17002502
  12. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.
    Nat Genet. 2005 Apr;37(4):391-400 PMID: 15765097
  13. Involvement of human MOF in ATM function.
    Mol Cell Biol. 2005 Jun;25(12):5292-305 PMID: 15923642
  14. A proapoptotic caspase recruitment domain protein gene, TMS1, is hypermethylated in human breast and gastric cancers.
    Anticancer Res. 2002 Nov-Dec;22(6C):4163-8 PMID: 12553049
  15. Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island.
    Genes Dev. 1994 Oct 1;8(19):2282-92 PMID: 7958895
  16. Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation.
    J Biol Chem. 1997 Aug 29;272(35):22322-9 PMID: 9268383
  17. Activation of a caspase-9-mediated apoptotic pathway by subcellular redistribution of the novel caspase recruitment domain protein TMS1.
    Cancer Res. 2000 Nov 15;60(22):6243-7 PMID: 11103777
  18. DNA methylation, nucleosome formation and positioning.
    Brief Funct Genomic Proteomic. 2005 Feb;3(4):351-61 PMID: 15814025
  19. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.
    Nat Genet. 1998 Jun;19(2):187-91 PMID: 9620779
  20. CpG-rich islands and the function of DNA methylation.
    Nature. 1986 May 15-21;321(6067):209-13 PMID: 2423876
  21. Effects of methylation on expression of TMS1/ASC in human breast cancer cells.
    Oncogene. 2003 May 29;22(22):3475-88 PMID: 12776200
  22. Control of histone modifications.
    J Cell Biochem. 1999;Suppl 32-33:141-8 PMID: 10629113
  23. Yeast heterochromatin: regulation of its assembly and inheritance by histones.
    Cell. 1998 May 1;93(3):325-8 PMID: 9590166
  24. Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer.
    Int J Cancer. 2003 Aug 20;106(2):198-204 PMID: 12800194
  25. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation.
    PLoS Genet. 2006 Mar;2(3):e40 PMID: 16596166
  26. De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase.
    Mol Cell Biol. 1996 Aug;16(8):4555-65 PMID: 8754856
  27. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16.
    Mol Cell Biol. 2005 Nov;25(21):9175-88 PMID: 16227571
  28. Nucleosome positioning signals in the DNA sequence of the human and mouse H19 imprinting control regions.
    J Mol Biol. 2003 Jan 31;325(5):873-87 PMID: 12527297
  29. Dual role of TMS1/ASC in death receptor signaling.
    Oncogene. 2006 Nov 2;25(52):6948-58 PMID: 16715133
  30. Different sensitivities of bromodomain factors 1 and 2 to histone H4 acetylation.
    Mol Cell. 2003 Feb;11(2):353-63 PMID: 12620224
  31. Methylation-mediated silencing of TMS1/ASC is accompanied by histone hypoacetylation and CpG island-localized changes in chromatin architecture.
    J Biol Chem. 2002 Feb 15;277(7):4951-8 PMID: 11733524
  32. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF.
    Cell. 2005 Jun 17;121(6):873-85 PMID: 15960975
  33. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells.
    Mol Cell Biol. 2005 Aug;25(15):6798-810 PMID: 16024812
  34. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells.
    J Biol Chem. 1999 Nov 26;274(48):33835-8 PMID: 10567338
  35. TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers.
    Cancer Res. 2000 Nov 15;60(22):6236-42 PMID: 11103776
  36. Role of histone H3 lysine 27 methylation in X inactivation.
    Science. 2003 Apr 4;300(5616):131-5 PMID: 12649488
  37. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer.
    Mol Cell Biol. 2003 Jan;23(1):206-15 PMID: 12482974
  38. High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines.
    Cell. 1990 Aug 10;62(3):503-14 PMID: 1974172
  39. Methylation of ASC/TMS1, a proapoptotic gene responsible for activating procaspase-1, in human colorectal cancer.
    Cancer Lett. 2003 Dec 8;202(1):101-8 PMID: 14643031
  40. Cancer epigenomics: DNA methylomes and histone-modification maps.
    Nat Rev Genet. 2007 Apr;8(4):286-98 PMID: 17339880
  41. Aberrant silencing of the CpG island-containing human O6-methylguanine DNA methyltransferase gene is associated with the loss of nucleosome-like positioning.
    Mol Cell Biol. 1997 Oct;17(10):5813-22 PMID: 9315639
  42. Genomic maps and comparative analysis of histone modifications in human and mouse.
    Cell. 2005 Jan 28;120(2):169-81 PMID: 15680324
  43. Switching on chromatin: mechanistic role of histone H4-K16 acetylation.
    Cell Cycle. 2006 Jul;5(13):1361-5 PMID: 16855380
  44. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin.
    Nat Genet. 2002 Nov;32(3):378-83 PMID: 12379856
  45. Nucleosomes are translationally positioned on the active allele and rotationally positioned on the inactive allele of the HPRT promoter.
    Mol Cell Biol. 2001 Nov;21(22):7682-95 PMID: 11604504
  46. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27.
    Genes Dev. 2004 Jul 1;18(13):1592-605 PMID: 15231737
  47. A genomic code for nucleosome positioning.
    Nature. 2006 Aug 17;442(7104):772-8 PMID: 16862119
  48. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin.
    Genes Dev. 2004 Jun 1;18(11):1251-62 PMID: 15145825
  49. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation.
    Cell. 2001 Dec 14;107(6):727-38 PMID: 11747809
  50. The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis.
    Mol Cell Biol. 2008 Jan;28(1):397-409 PMID: 17967868
Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-0141
Published
2008-08-15
Pages
6810-21
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC2585755
Subset
IM
Grants
NCI NIH HHS · 2R01-CA077337 · United States
NCI NIH HHS · R01 CA132065 · United States
NCI NIH HHS · R01 CA077337-09 · United States
NCI NIH HHS · R01 CA077337 · United States
NCI NIH HHS · R01 CA077337-08 · United States
NCI NIH HHS · R01 CA077337-10 · United States
NCI NIH HHS · R01 CA077337-07 · United States
NCI NIH HHS · R01 CA077337-06A1 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-08-0141 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2