H2AK119Ub1 and H3K27Me3 in molecular staging for survival prediction of patients with pancreatic ductal adenocarcinoma

Abstract

Polycomb group (PcG) proteins Ring1B and EZH2, which have been characterized as catalyzing the two epigenetic modifications H2AK119 monoubiquitination (H2AK119Ub1) and H3K27 trimethylation (H3K27Me3), are well-known epigenetic silencers implicated in embryonic development and tumorigenesis. However, the status of polycomb-associated histone modifications and their clinical implications in pancreatic cancer remain unclear. Here, we performed immunohistochemistry on tissue microarrays (TMAs) containing 80 pairs of human pancreatic cancer specimens to assess the expression levels of Ring1B, H2AK119Ub1, EZH2, and H3K27Me3 in tumors. More than 50% of the tumor cells showed a high expression of H2AK119Ub1, Ring1B, and EZH2, whereas more than 50% of the tumor cells showed a low level of H3K27Me3. Different expression patterns of H2AK119Ub1 and H3K27Me3 in tumors were negatively correlated (r = −0.247, P = 0.027). Both H2AK119Ub1 and H3K27Me3 independently predicted the clinical prognosis. In particular, a combinatorial pattern of elevated H2AK119Ub1 and decreased H3K27Me3 in tumors was significantly correlated with a poorer prognosis. Furthermore, compared to the tumor, lymph node, metastasis (TNM) staging system, histone modifications can discriminate the survival difference more accurately, especially for patients with stage I or stage II tumors. Simultaneous silencing of Ring1B and EZH2 via shRNA depleted H2AK119Ub1 and H3K27Me3 in the pancreatic cancer cells PanC1 and AsPC1, enhanced HOX gene derepression, and inhibited tumor cell growth in vitro and in tumor xenograft models. These results demonstrated that H2AK119Ub1 and H3K27Me3 cooperate in tumors and are associated with the clinical prognosis in combinatorial patterns. We have proposed that epigenetic modifications may serve as discriminatory biomarkers for molecular staging of pancreatic cancer.

Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2

“…Intriguingly, we and others have observed a decoupling of EZH2 expression levels from H3K27me3 levels in cancers515253. In ADC regions, high and uniform H3K27me3 was found with relatively low expression of EZH2.…”

Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

“…Histone ubiquitination has also been implicated in pancreatic homeostasis and pancreatic cancer tumorigenesis [71,72,73]. Histone ubiquitination mainly occurs on H2A and H2B and leads to mostly their mono-ubiquitination which does not lead to protein degradation but alters nucleosome dynamics and cross-talk between other histone modifications [74,75].…”

“…However, the presence of Ring1 and Bim1 greatly stimulates the ligase activity of Ring2 for H2A. Studies have found that over 50% of PDA tissues have increased expression of H2AK119 monoubiquitination (H2AK119Ub1) and Ring2 [73]. In addition, H2AK119Ub1 is an independent predictor of clinical prognosis.…”

“…In addition, H2AK119Ub1 is an independent predictor of clinical prognosis. High expression of H2AK119Ub1 was found to be significantly associated with larger tumor size, poor differentiation, and lymph node metastasis [73]. Silencing of Ring2 in PDA cells depleted H2AK119Ub1 and inhibited tumor cell growth.…”

Implication of epigenetics in pancreas development and disease

“…MBD1 forms a complex with Twist and NAD-dependent deacetylase SIRT-1 on the CDH1 promoter, which results in epigenetic downregulation of E-cadherin and increased epithelial-to-mesenchymal transition [94]. Bmi1, Ring1b and Ezh2 are upregulated in PDAC, and H2AK119Ub1 and H3K27Me3 marks may serve as discriminatory biomarkers for PDAC staging [33] and [95]. The genomic landscape of PDAC human cell lines, explored by ChIP-seq and RNA-seq, reveals regions with an enrichment of positive marks (H3K4me1, H3K4me3, RNA Pol II) and a depletion of negative marks (H3K27me3), in correlation with gene expression.…”