Global levels of histone modifications predict prognosis in different cancers.
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.
Departments of Pathology and Laboratory Medicine,Human Genetics, David GeffenSchool of Medicine, University of California, Los Angeles, California 90095-1737, USA. skurdistani@mednet.ucla.edu
David B
DB
Seligson
Steve
S
Horvath
Matthew A
MA
McBrian
Vei
V
Mah
Hong
H
Yu
Sheila
S
Tze
Qun
Q
Wang
David
D
Chia
Lee
L
Goodglick
Siavash K
SK
Kurdistani
D000107:Acetylation; D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012091:Repetitive Sequences, Nucleic Acid; D046888:Tissue Array Analysis
D006657:Histones