The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

Sasaki, Motoko; Ikeda, Hiroko; Itatsu, Keita; Yamaguchi, Junpei; Sawada, Seiko; Minato, Hiroshi; Ohta, Tetsuo; Nakanuma, Yasuni

doi:10.1038/labinvest.2008.52

Cited by 121 publications

(97 citation statements)

References 32 publications

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“…BMI1 knockdown by siRNA results in inhibition of cell proliferation (23)(24)(25), the same as knockdown of EZH2. Thus, the polycomb group proteins EZH2 and BMI1 have been implicated in the progression of human cancers, and both proteins have been regarded as possible targets of treatment (27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 95%

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Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus

et al. 2011

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Abstract. EZH2 and BMI1 are transcriptional repressors and have been implicated in the progression of human cancers. Squamous cell carcinoma of the esophagus (ESCC) is one of the most aggressive carcinomas in the gastrointestinal tract and generally has an unfavorable outcome. In the present study, we immunohistochemically investigated the expression of EZH2 and BMI1 in 136 surgically resected ESCCs and adjacent epithelium. We also analyzed associations between aberrant expression of EZH2 and BMI1, and both clinicopathological findings and outcome. MYC, RB, and P53 expression was examined in selected cases and analyzed in relation to EZH2 expression. Mutations in the P53 gene were evaluated by direct sequencing. EZH2 mRNA expression was investigated in ESCC cell lines with and without P53 transcriptional activity. The results showed that EZH2 protein and BMI1 protein were upregulated in ESCC tissue in comparison with adjacent non-neoplastic epithelium. Aberrant EZH2 and BMI1 protein expression was observed in 19 (14.0%) and 23 (16.9%), respectively, of the 136 ESCCs. Aberrant EZH2 expression was significantly associated with larger size, greater depth of invasion, presence of distant metastasis, and shorter disease-free survival time. Aberrant BMI1 expression was inversely associated with lymph node metastasis and venous invasion, but not associated with survival of the patients. In addition, aberrant EZH2 expression was associated with P53 alteration in ESCC tissue. EZH2 mRNA expression in ESCC cell lines was reduced by activation of P53. In conclusion, P53 alteration may be involved in dysregulated EZH2 expression, and aberrant expression of EZH2 may play a role in ESCC progression.

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Section: Introductionmentioning

confidence: 95%

“…BMI1 has also been reported to be overexpressed in several human cancer types (21)(22)(23)(24)(25)(26). BMI1 knockdown by siRNA results in inhibition of cell proliferation (23)(24)(25), the same as knockdown of EZH2.…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus

et al. 2011

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“…PcG proteins Bmi1 and EZH2 are epigenetic chromatin modifiers involved in cancer development (18), and the high EZH2 expression localized to primitive malignant cell types is often combined with a high Bmi1 expression (19,20). EZH2 may mediate increased invasiveness and metastasis by silencing downstream target adrenergic receptor β-2 (ADRB2) (21).…”

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confidence: 99%

The expression and significance of the enhancer of zeste homolog 2 in lung adenocarcinoma

Yuan

Xiao

et al. 2012

Oncol Rep

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Abstract. Lung adenocarcinoma, with increased incidence in the world, exhibits poor prognosis and is usually resistant to conventional chemotherapy due to drug resistance. The enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in tumorigenesis and cancer development through chromatin remodeling in various types of cancer. However, its potential role in lung adenocarcinoma has not been well defined. In this study, the expression of EZH2 was examined in lung adenocarcinoma tissues and cell lines. Most interestingly, EZH2 overexpression was detected in tumor tissue and significantly correlated with histological differentiation, pathological tumor-node-metastasis stage and smoking history, but not with gender or age. Furthermore, EZH2 overexpression was also detected in cisplatin-resistant cancer cells rather than cisplatin-sensitive cells. Short hairpin RNA targeted against EZH2 inhibited cell proliferation and migration, and led to G(2)/M cell cycle arrest and apoptosis in both cisplatin-resistant and cisplatin-sensitive cell lines. Moreover, EZH2 knockdown enhanced cisplatin sensitivity of cisplatin-resistant cells and reduced the expression levels of multidrug resistance-related protein 1. Our study suggests that EZH2 contributes to the progression of lung adenocarcinoma, and the deletion of EZH2 inhibits cancer and resensitizes cells to cisplatin in lung adenocarcinoma.

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“…12 In the oncogenic setting, the Ink4a-retinoblastoma protein (Rb) and Arf-p53 cellular senescence pathways trigger oncogene-induced senescence to eliminate transforming cells that potentially develop into cancer stem cells. 2 Given that enhanced expression of BMI1 and reduced expression of INK4A/ARF are frequently observed in human hepatocellular carcinoma (HCC) samples, 13,14 it would be of importance to understand the contribution of the Ink4a/Arf locus to the oncogenic functions of Bmi1 in cancer and search for as-yet-unknown target genes of Bmi1 other than Ink4a/Arf.…”

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Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

et al. 2010

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We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1 2/2 Deltalike protein (Dlk) 1 hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf 2/2 Dlk 1 cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk 1 cells. Although Ink4a/Arf 2/2 Dlk 1 cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf 2/2 Dlk 1 cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five downregulated genes as candidate downstream targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk 1 cells strongly suppressed colony propagation and tumor growth. Conclusion: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells.

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The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

Cited by 121 publications

References 32 publications

Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus

Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus

The expression and significance of the enhancer of zeste homolog 2 in lung adenocarcinoma

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

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