Polycomb group protein EZH2‐mediated E‐cadherin repression promotes metastasis of oral tongue squamous cell carcinoma

Huang

et al. 2017

Oncol Lett

Section: Discussionmentioning

confidence: 99%

Epigenetic analysis of FHL1 tumor suppressor gene in human liver cancer

Huang

et al. 2017

Oncol Lett

“…Overexpression of EZH2 significantly correlated with tumor size, cervical lymph node metastasis, clinical stage and poor prognosis, and served as an independent prognostic indicator for patients with head neck cancer [23-25]. However, the in-depth investigations into the expression pattern of EZH2 and associated molecular mechanisms underlying TSCC development has been in infancy and remains to be further clarified.…”

Section: Introductionmentioning

confidence: 99%

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

Qiu

et al. 2013

Oncotarget

EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer.

“…Tca8113 was previously established at Shanghai Jiaotong University (a generous gift from Professor Wantao Chen). 31 The Cal27, SCC9 and SCC25 cells were purchased from American Type Culture Collection (ATCC). Cancerous cell lines were grown in DMEM (Invitrogen) supplemented with 10% FBS (Gibco) and 100 units/ml penicillin and streptomycin, and maintained in a humidified incubator with 5% CO 2 at 37 1 C. The HDACis TSA and NaB were purchased from Sigma Aldrich (category number: T8552, B5887) and dissolved in DMSO or PBS as stocking solutions and diluted with culture medium upon addition into cells.…”

mentioning

confidence: 99%

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

Laboratory Investigation

Yuan

et al. 2014

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, ...