Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 May;174(5):1619-28.
doi: 10.2353/ajpath.2009.080874. Epub 2009 Apr 6.

Global levels of histone modifications predict prognosis in different cancers

David B Seligson  1 , Steve Horvath, Matthew A McBrian, Vei Mah, Hong Yu, Sheila Tze, Qun Wang, David Chia, Lee Goodglick, Siavash K Kurdistani
Affiliations

Global levels of histone modifications predict prognosis in different cancers

David B Seligson et al. Am J Pathol. 2009 May.

Abstract

Cancer cells exhibit alterations in histone modification patterns at individual genes and globally at the level of single nuclei in individual cells. We demonstrated previously that lower global/cellular levels of histone H3 lysine 4 dimethylation (H3K4me2) and H3K18 acetylation (ac) predict a higher risk of prostate cancer recurrence. Here we show that the cellular levels of both H3K4me2 and H3K18ac also predict clinical outcome in both lung and kidney cancer patients, with lower levels predicting significantly poorer survival probabilities in both cancer groups. We also show that lower cellular levels of H3K9me2, a modification associated with both gene activity and repression, is also prognostic of poorer outcome for individuals with either prostate or kidney cancers. The predictive power of these histone modifications was independent of tissue-specific clinicopathological variables, the proliferation marker Ki-67, or a p53 tumor suppressor mutation. Chromatin immunoprecipitation experiments indicated that the lower cellular levels of histone modifications in more aggressive cancer cell lines correlated with lower levels of modifications at DNA repetitive elements but not with gene promoters across the genome. Our results suggest that lower global levels of histone modifications are predictive of a more aggressive cancer phenotype, revealing a surprising commonality in prognostic epigenetic patterns of adenocarcinomas of different tissue origins.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Cellular heterogeneity in levels of histone modifications in primary cancer tissues. Immunohistochemical staining of cancer tissues from lung adenocarcinoma (grade 2) (A) and kidney clear cell carcinoma (grade 1) (B) with an anti-H3K18ac antibody. Percentage of cancer cells with brown nuclei determines the global levels of each histone modification for a given individual. Distribution of patients for the levels of H3K4me2 (black bars) and H3K18ac (gray bars) in cancer tissues from lung (C) and kidney (D) are shown. The graphs represent the fraction of patients (y axis) with indicated levels of histone modifications as percent cell staining (x axis). Original magnifications: ×10 (A, B; left); ×40 (A, B; right).
Figure 2
Figure 2
Prediction of clinical outcome in different carcinomas by histone modifications. For each cancer type, patients were first assigned to two groups based on the levels of H3K4me2 and H3K18ac, and then their clinical outcomes were compared. Kaplan-Meier plots are used to visualize survival probabilities of the two groups (group 1, black line; group2, red line) in lung (A) (log rank, P = 0.018, n = 159) and kidney (B) (log rank, P = 0.028, n = 192). Tabulated in the insets is the distribution of the patients in each group according to grade.
Figure 3
Figure 3
The cellular levels of H3K9me2 predict clinical outcome in prostate and kidney cancers. Distribution of patients for the levels of H3K9me2 in cancer tissues from prostate (A) and kidney (C) are shown. The graphs represent the fraction of patients (y axis) with indicated levels of histone modifications as percent cell staining (x axis). For each cancer type, patients were first assigned to two groups based on the levels of H3K9me2, and then their clinical outcomes were compared (group 1, H3K9me2 >10%, black line; group 2, H3K9me2 ≤10%, red line). Kaplan-Meier plots are used to visualize the difference in outcome of the two groups in low-grade prostate (B) (log rank, P = 0.0043, n = 109) and all kidney (D) (log rank, P = 0.00092, n = 359) cancer patients. Tabulated in the insets is the distribution of the patients in each group according to grade.
Figure 4
Figure 4
Cellular heterogeneity in levels of histone modifications in cancer cell lines. A: Immunohistochemical examination of H3K9me2 in LNCaP and PC3 prostate cancer cell lines. Note the increased percentage of PC3 cells with lower levels of H3K9me2 (blue nuclei) compared with LNCaP cells. B: Western blot of acid-extracted histones from LNCaP and PC3 cells for H3K9me2 levels and histone H3 (irrespective of modifications) as a loading control. The triangles indicate increased loading from left to right.
Figure 5
Figure 5
Global levels of H3K9me2 correlates with its levels at repetitive DNA elements. A: ChIP-chip analysis of H3K9me2 in LNCaP and PC3 cells. Each row represents the region from −5.5 to +2.5 of annotated transcription start site (TSS) for a given gene that is divided into 16 fragments of 500 bp each. Genes are grouped based on similarity of e1a-binding pattern across the 8-kb promoter region. The colors indicate relative enrichment or depletion of ChIPed DNA (yellow) versus input (blue) from each cell. B: Correlations of H3K9me2 levels at each of the 16 fragments across all promoters between LNCaP and PC3 cells. C: ChIP quantitative real-time PCR analyses of the levels of H3K9me2 and H3K18ac at the indicated DNA repetitive elements. The values are represented as percentage of input. The error bars represent SD of three independent experiments. Histone H3 ChIP was used as a control to show that lower modification levels in PC3 cells are not attributable to nucleosome loss.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Baylin SB, Ohm JE. Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer. 2006;6:107–116. - PubMed
    1. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4:143–153. - PubMed
    1. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692. - PMC - PubMed
    1. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature. 1998;391:597–601. - PubMed
    1. Hake SB, Xiao A, Allis CD. Linking the epigenetic ‘language’ of covalent histone modifications to cancer. Br J Cancer. 2004;90:761–769. - PMC - PubMed

Publication types

MeSH terms

-