Increased Trimethylation of histone H3K36 associates with biliary differentiation and predicts poor prognosis in resectable hepatocellular carcinoma

Abstract

IntroductionTrimethylation of histone H3K36 (H3K36me3), an epigenetic marker of transcription-associated histone modification and stem cell regulation, is expressed in a variety of human cancers. This study elucidated the prognostic significance of H3K36me3 in patients with resectable hepatocellular carcinoma (HCC).MethodsExpression of H3K36me3 was retrospectively evaluated through immunohistochemistry in 152 surgically resected primary HCCs.ResultsIn nontumorous liver parenchyma, H3K36Me3 was detected in bile ducts but not in hepatocytes. H3K36me3 was positive in 104 (68.4%) of the HCCs. Positivity for H3K36me3 was associated with high level of serum α-fetoprotein (>200 ng/mL, P = 0.0148), high tumor grade (P = 0.0017), and high tumor stage (P = 0.0008). Patients with H3K36me3-positive tumors were more likely to have lower 5-year disease-free survival and 5-year overall survival than those with H3K36me3-negative tumors (P = 0.0484 and P = 0.0213, respectively). Multivariate analysis showed that H3K36me3 positivity was an independent predictor of high tumor grade (P = 0.0475) and high tumor stage (P = 0.0114) and thus contributed to poor prognosis. Furthermore, H3K36me3 positivity was significantly correlated with the expression of biliary markers cytokeratin 19 (CK19) and hepatocyte nuclear factor 1β (HNF1β) (P < 0.0001 and P = 0.0005, respectively). Combinatorial analysis revealed that CK19 and HNF1β expression individually exerted additive prognostic adverse effects on HCCs with H3K36me3 positivity.ConclusionsOur study indicates that H3K36me3 positivity is associated with the expression of biliary markers and is a crucial predictor of poor prognosis in resectable HCC.

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“…Histone modification is one of the epigenetic changes that regulate the chromatin structure and, therefore, impact diverse DNA-templated procedures [4]. Accumulating studies have demonstrated that changes in histone modification occurred in different types of human malignant tumours and having value in clinical practice, such as markers for predicting prognosis, assessing therapeutic response to some chemotherapeutic drugs, and emerging therapeutic targets for treating cancers [5][6][7]. There are five histone families in human, i.e.…”

Microarray-based Analysis of Genes, Transcription Factors, and Epigenetic Modifications in Lung Cancer Exposed to Nitric Oxide

“…H3K36me3 was shown to have the highest degree of epigenetic modification hubs that were altered by NO exposure. H3K36me3 was also found to be associated with a poor prognosis in hepatocellular carcinoma (60) and corelated with cancer-related gene expression in cancer cell lines (61). In addition, H3K79Me3 is one of the histone modifications of interest due to controlling epithelial-to-mesenchymal (EMT) (62) and the stemness of certain cells (63).…”

Clinicopathologic significance of protein lysine methyltransferases in cancer

“…H3K36, which refers to lysine 36 from the N-terminus of histone H3, is associated with actively transcribed genes, especially when it undergoes tri-methylation (H3K36me3) [60]. H3K36me3 is thought to function in DNA mismatch repair, modulation of chromatin structure, and stem cell regulation [60]. SETD2 is the only methyltransferase thought to tri-methylate H3K36 in the literature [66].…”

“…Interestingly, similar to the prognostic significance of H3K27me3, H3K36me3 expression levels have been correlated with both better or worse survival in different cancer types. Lien et al demonstrated that in HCC, H3K36me3 positivity on immunostaining is not only a predictor of high tumor grade and stage, but is also a contributor to tumor recurrence and poor survival [60]. In contrast, Ho et al discovered that even when adjusting for age and a validated prognostic scoring, loss of H3K36me3 expression was associated with higher risk of renal cell carcinoma-specific death and progression after nephrectomy in clear cell renal cell carcinoma patients [61].…”