Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma

Abstract

Epigenetic alterations play an important role in carcinogenesis. Recent studies suggested that global histone modifications are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone H3 lysine 4 monomethyl (H3K4me1), -di-methyl (H3K4me2) and -trimethyl (H3K4me3) patterns in renal cell carcinoma (RCC) using a tissue microarray with 193 RCC (including 142 clear cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC) and 10 oncocytoma specimens: H3K4me3 staining was more intense in papillary RCC, whereas H3K4me1 and H3K4me2 were similar in the diverse RCC subtypes. H3K4me2 and H3K4me3 levels were increased in oncocytoma. H3K4me1-3 levels were inversely correlated with Fuhrman grading, pT stage, lymph node involvement and distant metastasis. Progression-free survival and cancer-specific survival were shorter in patients with low levels of H3K4me1-3 in the univariate analysis, but we did not observe a significant correlation of a single modification in a multivariate model, which also included the established prognostic parameters TNM-stage and Fuhrman grade. In comparison, the H3K4me score, which combined staining levels of the H3K4 modifications, was an independent predictor of RCC progression-free survival. Our study on H3K4 methylation supports the concept of global histone modifications as potential cancer prognosis markers.In 2009, 57,760 new cases and 12,980 deaths of kidney cancer were estimated in the United States. 1 Renal cell carcinoma (RCC) is a heterogeneous group of histological subtypes, of which clear cell RCC (ccRCC) is the most common, comprising more than 85% of all cases; papillary (pRCC, 10%), chromophobe (chRCC, 3%) and sarcomatoid renal cell carcinoma (sRCC) are less common. 2 The clinical outcome of patients with RCC is mainly depending on TNM stage, Fuhrman grade and the Eastern Cooperative Oncology Group (ECOG) performance status. 2 However, RCC patients with similar tumor characteristics still show heterogeneity in the course and outcome of cancer. Therefore, a subclassification of patients with similar clinical and pathological variables is necessary, and may also allow the development of novel therapies.Epigenetic alterations are common in solid tumors, and they lead to silencing of various tumor suppressor genes. 3 DNA methylation has been widely studied, and tumor suppressor gene CpG island hypermethylation was identified as an important step during renal cell carcinogenesis. 4 Histone modifications are also important regulators of transcriptional activity; so far, they have been less comprehensively studied in RCC despite the fact that changes in DNA methylation are closely related to histone alterations. 5 Post-translational modifications (i.e., acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP-ribosylation and deimination) occur on the N-terminal tail of the histone. 6 The modifications function either by disrupting chromatin contacts or by affecting the recruitment of various proteins to the chromatin, and...

Histone onco-modifications

“…A decrease of H3K4me2/me3 is observed in a range of neoplastic tissues and may serve as a predictive factor for clinical outcome for some of them (Seligson et al, 2005;Barlesi et al, 2007;Elsheikh et al, 2009;Ellinger et al, 2010;Manuyakorn et al, 2010;Rajendran et al, 2011). In particular, tumor recurrence occurs earlier in low-grade prostate carcinoma patients with low H3K4me2, independently of other clinical and pathologic parameters (Seligson et al, 2005).…”

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

“…For example, trimethylation of Histone H3 at the Lysine 4 residue (H3K4me3) is a wellcharacterized histone mark that is enriched at gene transcriptional start sites (TSS) and is associated with transcriptionally active genes (16)(17)(18)(19). Levels of H3K4me3 are globally and locally altered during different developmental stages of cancer, and can serve as a predictor for disease recurrence (20)(21)(22)(23)(24)(25)(26). It was also recently determined that increased H3K4me3 and decreased H3K27me3 is important for activation of genes linked to proliferation and invasion of breast cancer such as matrix metalloproteinases (MMP), ERBB3, Six1, Cyclin A1, Pim-1, and CSPG4 (14).…”

New insights on chromatin modifiers and histone post‐translational modifications in renal cell tumours

“…Although, in univariate analysis, low levels of all states of H3K4 methylation were predictive of progression-free and cancer-specific survival, in a multivariate analysis, no statistical significance was depicted [16]. However, an H3K4me score, empirically established by the authors, was an independent predictor of progression-free survival in patients with RCC, independently of pathological stage and Fuhrman grade [16]. Similar results have been reported in a different study, in which lower levels of H3K4me2 was significantly associated with decreased disease survival [14].…”

“…H3K4me2 levels were also associated with the presence of lymph node metastasis (P = 0Á018) [16] H3K4me2 Prognostic Expression 189 localized RCCs H3K4me2 levels grouped with H3K18Ac were independent predictors of outcome in localized RCC (P = 0Á034) (inversely correlation) [15] H3K9me2 NS Expression HEK 293 cell line Hypoxia increased global H3K9me2 levels and augmented the methyltransferase G9a activity [13] Prognostic Expression 359 RCC and 189 localized RCC H3K9me2 levels were independent predictors of outcome in all RCC (P = 0Á026) and localized RCC (P = 0Á028) (inversely correlation) [15] H3K27me1; H3K27me2; H3K27me3…”

“…It was shown that different di-(H3K4me2) and trimethylation (H3K4me3) levels were significantly higher in oncocytomas compared to RCC [16]. However, lower H3K4 methylation (mono-, di-and trimethylation) levels were associated with adverse clinicopathological parameters such as more advanced pathological stage and higher Fuhrman grade, as well as with distant metastasis and lymphatic invasion, although the former only associated with H3K4me2 levels [16]. Although, in univariate analysis, low levels of all states of H3K4 methylation were predictive of progression-free and cancer-specific survival, in a multivariate analysis, no statistical significance was depicted [16].…”