High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer

Chen, Xiaohui; Song, Ning; Matsumoto, Keitaro; Nanashima, Atsushi; Nagayasu, Takeshi; Hayashi, Tomayoshi; Ying, Mingang; Endo, Daisuke; Wu, Zhiren; Koji, Takehiko

doi:10.3892/ijo.2013.2062

Cited by 53 publications

(62 citation statements)

References 46 publications

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“…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.…”

Section: Discussionmentioning

confidence: 44%

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

et al. 2017

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Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.

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Section: Discussionmentioning

confidence: 44%

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

et al. 2017

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“…In this study, we investigated the expression of three PcG proteins (EZH2, BMI1 and SUZ12) and associated histone modification H3K27me3 in colorectal cancer tissues. Aberrant expression of each of these histone-modifying enzymes, and of histone modification H3K27me3, has been indicated to contribute to tumorigenesis in several types of cancer and has been correlated to patient outcome [11]–[24]. Studies in literature show conflicting results regarding the prognostic value of the Polycomb group proteins in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

“…SUZ12 polycomb repressive complex 2 subunit (SUZ12), another key component of the PRC2 complex, was found to have tumor-promoting functions in several cancers, including colon cancer [21]–[23]. The associated histone modification H3K27me3 was found to be higher expressed in tumor tissues, and to be associated with better prognosis in non-small cell lung cancer [24] and breast cancer [19].…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of Polycomb Proteins EZH2, BMI1 and SUZ12 and Histone Modification H3K27me3 in Colorectal Cancer

et al. 2014

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Numerous changes in epigenetic mechanisms have been described in various types of tumors. In search for new biomarkers, we investigated the expression of Polycomb-group (PcG) proteins EZH2, BMI1 and SUZ12 and associated histone modification H3K27me3 in colorectal cancer. Nuclear expression of PcG proteins and histone modification H3K27me3 were immunohistochemically (IHC) stained on a tissue microarray (TMA), including 247 tumor tissues and 47 normal tissues, and scored using the semi-automated Ariol system. Tumor tissues showed higher expression of EZH2 (p = 0.05) and H3K27me3 (p<0.001) as compared to their normal counterparts. Combined marker trend analyses indicated that an increase in the number of markers showing high expression was associated with better prognosis. High expression of all four markers in the combined marker analyses was correlated with the best patient survival and the longest recurrence-free survival, with overall survival (p = 0.01, HR 0.42(0.21–0.84)), disease-free survival (p = 0.007, HR 0.23(0.08–0.67) and local recurrence-free survival (p = 0.02, HR 0.30(0.11–0.84)). In conclusion, we found that expression of PcG proteins and H3K27me3 showed prognostic value in our study cohort. Better stratification of patients was obtained by combining the expression data of the investigated biomarkers as compared to the individual markers, underlining the importance of investigating multiple markers simultaneously.

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“…Consistently, Ezh2 inhibition enhances the sensitivity of TopoII inhibitor in EGFG and BRIG mutant NSCLC mouse models, but has no effect in the NSCLC mouse model with Kras and p53 mutations 19. On the other hand, two separate reports show that the decreased levels of H3K27me3 and EZH2 are associated with poor prognosis in human lung ADC patients 20, 21. Furthermore, embryonic ectoderm development (Eed), another component of PRC2, exhibits the tumor-suppressive function in the formation of Kras-p53-double- mutant NSCLC in mice 22.…”

Section: Introductionmentioning

confidence: 93%

Ezh2 Acts as a Tumor Suppressor in Kras-driven Lung Adenocarcinoma

Wang¹,

Hou²,

Chen³

et al. 2017

Int. J. Biol. Sci.

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Previous studies have suggested that enhancer zeste homolog 2 (Ezh2), a histone methyltransferase subunit of polycomb repressive complex 2 (PRC2), acts as an oncogene in lung adenocarcinoma (ADC) development. However, we found that in human lung ADC samples, deletion and mutations of EZH2 were also frequently present, with 14% of patients harboring loss-of-function EZH2 alterations. To explore the effect of Ezh2 loss on lung tumor formation, lung epithelial Ezh2 gene was deleted in Kras-driven lung ADC mouse model. Unexpectedly, Ezh2 loss dramatically promoted Kras-driven ADC formation. KrasG12D/+;Ezh2fl/fl mice exhibited shorter lifespan, more tumor lesions and higher tumor burden than KrasG12D/+ mice, suggesting the tumor-suppressive role of Ezh2 in Kras-driven ADCs. Mechanistically, Ezh2 loss amplified Akt and ERK activation through de-repressing its target insulin-like growth factor 1 (Igf1). Additionally, Ezh2 loss cooperated with Kras mutation to exacerbate the inflammatory response, as shown by massive macrophage and neutrophil infiltrates, as well as a marked increase in tumor-associated cytokines such as IL-6 and TNF-α. Taken together, our findings revealed the tumor suppressive function of Ezh2 in Kras-driven ADCs, underlining the importance of revaluating the application of EZH2 inhibitors in a variety of cancers.

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High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer

Cited by 53 publications

References 46 publications

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

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

Prognostic Value of Polycomb Proteins EZH2, BMI1 and SUZ12 and Histone Modification H3K27me3 in Colorectal Cancer

Ezh2 Acts as a Tumor Suppressor in Kras-driven Lung Adenocarcinoma

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