The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer

li, Zhongwu; Wang, Yanling; Qiu, Jing; Li, Qiang; Yuan, Chunping; Zhang, Wei; Wang, Dongmiao; Ye, Jinhai; Huang, Jiang; Yang, Jianrong; Cheng, Jie

doi:10.18632/oncotarget.1503

Cited by 68 publications

(76 citation statements)

References 53 publications

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“…33 Equal amounts of protein samples were loaded and separated by 8-12% SDS-PAGE and transferred to PVDF membranes (Millipore), which then were blocked by 5% non-fat dry milk. These blots were incubated at 4 1 C overnight with primary antibodies Bmi1, EZH2, p16, cleaved-PARP (Cell Signaling, 1:1000 dilution), E-cadherin, Vimentin (BD Biosciences, 1:2000 dilution) and GAPDH (Santa Cruz, 1:2000 dilution) followed by incubations with secondary antibodies.…”

Section: Western Blot Analysismentioning

confidence: 99%

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Wang

Yuan

et al. 2014

Laboratory Investigation

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The polycomb complex protein Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog) mediates epigenetic transcriptional silencing by modifying chromatin structure and is critical for stem cell homeostasis and tumorigenesis. Bmi1 is frequently overexpressed in human malignancies and therefore has key diagnostic and prognostic significance, and holds potential as a therapeutic target. Here we sought to characterize the expression patterns and oncogenic roles of Bmi1 in tongue squamous cell carcinoma and to determine the anticancer effects of histone deacetylase inhibitors (HDACis) via Bmi1 inhibition against tongue cancer. Our data revealed that Bmi1 was aberrantly overexpressed in a significant portion of tongue cancers. Elevated Bmi1 is associated with cervical node metastasis, Ki-67 abundance and reduced overall survival, and also serves as an independent prognostic factor for patient outcomes. Short-hairpin RNA-mediated Bmi1 knockdown inhibited cell proliferation and migration, induced cell apoptosis and senescence, reduced colony formation and CD44þ CD133 þ sub-population as well as enhanced cisplatin chemosensitivity, presumably by modulation of p16, p14 and E-cadherin. Moreover, HDACi chemicals Trichostatin A (TSA) and sodium butyrate (NaB) potently inhibited Bmi1 and triggered similar phenotypic changes reminiscent of Bmi1 silencing, although TSA treatment seemed paradoxically to induce some epithelial-mesenchymal transition-like changes in tongue cancer cells. Importantly, NaB-induced antitumor effects were partially attenuated by enforced Bmi1 overexpression in vitro. Genetic Bmi1 silencing and pharmacological inhibition of Bmi1 by NaB treatment significantly impaired tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that Bmi1 serves as a key driver and biomarker with multiple oncogenic functions underlying tongue tumorigenesis. Selected appropriate HDACi compounds like NaB may represent novel therapeutic agents against tongue cancer. Oral cancer is one of the most common cancers worldwide, approximately accounting for 3% of all malignancies in both sexes. It is widely represented as a heterogeneous tumor with aggressive phenotypes and behaviors. The major etiological risks for this malignancy include smoking and alcohol consumption and human papillomavirus infection. 1 The overwhelming majority of oral cancers arises from tongue and is pathologically identified as squamous cell carcinoma (SCC). 2 Despite tremendous advancement in multimodal therapies against oral cancers over the past decades, the overall 5-year survival rate with these devastating diseases, especially those with advanced diseases, has not been markedly improved. 3 Local relapse and cervical lymph node metastasis are recognized as the most prevalent factors affecting patients' survival. Although many oncogenes and tumor suppressors have been identified as key factors underlying oral tumorigenesis, however, no optimal and commonly accepted biomarkers have been established to facilitate disease diagnosis, ...

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Section: Western Blot Analysismentioning

confidence: 99%

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Wang

Yuan

et al. 2014

Laboratory Investigation

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“…25 Cell migration assay Cell migration assay was performed using transwell chambers (8-mm pore size, Corning). Cells were starved without serum overnight, then seeded in the upper chambers with serum-free medium.…”

Section: Dmba-induced Oscc Animal Modelmentioning

confidence: 99%

Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma

Wang¹,

Zhang²,

Zhang

et al. 2015

Cancer Biology & Therapy

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Abnormal glucose metabolism mediated by pyruvate kinase M2 (PKM2) fuels cancer overgrowth and propagation. However, its expression and oncogenic roles in in oral squamous cell carcinoma (OSCC) remains incompletely known. Here, we aimed to investigate the expression of PKM2, its prognostic values and oncogenic functions using 7,12-dimethyl-1,2-bezan-tracene (DMBA)-induced hamster buccal pouch SCC model, primary OSCC specimens as well as in vitro cellular assays. We found that in DMBA-induced OSCC model, negative PKM2 expression was commonly observed in normal epithelial, while more PKM2 abundance was detected in hyperplasia, dysplasia and SCC. Overexpression of PKM2 in a major fraction of OSCC significantly associated with tumor size (P D 0.027), cervical node metastasis (P D 0.004) and clinical stages (P D 0.000). Patients with increased PKM2 had remarkably reduced overall and disease-free survival. Multivariate survival analysis further revealed that PKM served as a critical independent prognostic factor for patients' overall survival. Furthermore, impaired cell proliferation and migration, and reduced apoptosis were detected upon PKM2 knockdown in HN4 and HN12 cells. Taken together, our findings reveal that PKM2 is critically involved in OSCC initiation and progression probably by promoting cell proliferation and migration as well as reducing apoptosis. Its overexpression correlates with aggressive clinicopathological features and poor patients' outcome.

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“…Additionally, p21 can act as a master effector of multiple tumor suppressor pathways on promoting anti-proliferative activities that are independent of the classical p53 tumor suppressor pathway. Subsequent tothe depletion of Ezh2 (a main component of PRC2), marked inhibition of cellular proliferation, G1 cell cycle arrest and accompanying upregulation of key cell-cycle regulators p16, p21 and p27 has been identified in lymphoma and tongue cancer (41,42). However, the role of these proteins in regulating the GC cell proliferation and cell cycle has not previously been investigated.…”

Section: Discussionmentioning

confidence: 99%

Rnf2 knockdown reduces cell viability and promotes cell cycle arrest in gastric cancer cells

et al. 2017

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Abstract. Rnf2 is a fundamental component of the polycomb repressive complex 1and acts as the really interesting new gene finger E3 ligase, which is responsible for histone 2A modification. Previous studies have shown that the ring finger protein 2 (Rnf2) is overexpressed in various types of tumor and has a close association with tumor development. However, few studies have been carried out into the expression and biological function of Rnf2 in gastric cancer cells. The present study measured the expression of Rnf2 in gastric cancer cells and normal epithelial gastric cells. The results demonstrate that Rnf2 is upregulated in gastric cancer cells. In addition, the knockdown of Rnf2 inhibited the cell viability and induced increased G1 phase followed by a substantial reduction of the G2/M phase. The expression levels of p21 and p27 were also significantly elevated by the knockdown of Rnf2. These results provide evidence of the oncogenic function of Rnf2 in gastric cancer, possibly through an inhibition of cellular proliferation and a delay of the G2/M phase. Therefore, Rnf2 may be a novel target for the prognosis and therapy of gastric cancer. IntroductionPolycomb group (PcG) proteins are epigenetic regulators for gene silencing at the transcription level, acting as important regulators of DNA repair, proliferation, embryonic differentiation and cell-fate maintenance during development and in adult tissue homeostasis (1-3). These proteins exist in at least two biochemically and functionally distinct PcG core complexes referred to as polycomb repressive complex (PRC) 1 and 2. PRC2, which is involved in the initiation of gene repression, mediates the trimethylation of histone H3 at Lys27 (H3K27me3) and consists of histone methyltransferase enhancer of zeste homolog 2 (EZH2), the polycomb repressive complex and embryonic ectoderm development (4,5). The mammalian PRC1, which is an ubiquitin E3 ligase complex, consists of polycomb (PC), polyhomeotic (PH), BMI1, ring finger protein (Rnf) 1A and 2 (Rnf2) (6), among which Rnf2 has been identified as the catalytic subunit (7). Rnf2, acts as the RING finger E3 ligase responsible for H2A modification in the PRC1 complex and influences early development and embryonic stem cell maintenance as well as cancer development (8,9). Recent evidence showed that Rnf2 is highly expressed in various types of tumor in comparison to normal tissue counterparts (10). Knockdown of Rnf2 in HeLa cells resulted in morphological changes and an inhibition of cellularproliferation (7), suggesting an oncogenic function of Rnf2. Additionally, it has been reported that Rnf2 can either directly or indirectly target a distinct, specific pathway involved in cell cycle control (11,12). However, in order to acquire a complete understanding of the mechanisms through which cancer progression is regulated by Rnf2, additional investigation is required.Normal cell cycle progression is tightly controlled by a variety of molecular checkpoints, which supervise the biological processes that take place in different...

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The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer

Cited by 68 publications

References 53 publications

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma

Rnf2 knockdown reduces cell viability and promotes cell cycle arrest in gastric cancer cells

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