Global histone modification patterns predict risk of prostate cancer recurrence

Abstract

Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications. Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.

Using nuclear morphometry to predict the need for treatment among men with low grade, low stage prostate cancer enrolled in a program of expectant management with curative intent

“…The authors demonstrate that the transformation of LNCaP cell lines with P300 gene and variations in expression of P300 among CaP cells collected from patients can produce alternations in nuclear size and shape [37]. Seligson et al [38] have shown that molecularly modified histones H3 (acetylated) and H4 (methylated) correlate with PSA-recurrence; however, the correlation with nuclear structure alterations has not been made. Further investigation has demonstrated that certain reproducible alterations of morphometric nuclear features were identified as a cell underwent malignant transformation and progression to metastasis, and these could be used clinically as biomarkers [22,39,40].…”

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

“…A first draft of an aberrant histone modification signature for human cancer has been produced Seligson et al, 2005). The next task is to identify the molecules involved in its establishment: histone acetyltransferases (HATs), histone methyltransferases (HMTs) and histone deacetylases (HDACs).…”

“…These two histone-modification losses can be considered as almost universal epigenetic markers of malignant transformation , as has now been accepted for global DNA hypomethylation and CpG island hypermethylation. Certain histone acetylation and methylation marks may have prognostic value (Seligson et al, 2005).…”

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

“…Substantial evidence supports the involvement of epigenetic processes in PrCa progression (Seligson et al, 2005). At the DNA level, multiple tumor suppressor genes involved in regulation of prostate differentiation, proliferation or metastasis are effectively silenced by promoter methylation; frequently detected already in premalignant lesions (Cooper and Foster, 2009).…”

“…Epigenetic changes in cancer progenitor cells may represent early or initial steps in tumorigenesis, resulting in polyclonal precursor populations prone to the accumulation of additional genetic and epigenetic defects (Holst et al, 2003). Furthermore, global changes in histone modification patterns are functionally associated with cancer development and recurrence (Fraga et al, 2005;Seligson et al, 2005Seligson et al, , 2009). These epigenetic modifications are mediated by antagonizing sets of enzymatic complexes: the 'writer' proteins, which attach chromatin modifications in a site-specific manner, and the 'eraser' proteins that remove these (Ruthenburg et al, 2007).…”