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

Abstract

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, ...

Involvement of 15-lipoxygenase-1 in the regulation of breast cancer cell death induced by sodium butyrate

“…This led us to study the effect of sodium butyrate on breast cancer cell growth and explore the possible involvement of 15-Lox-1 in the pathway that sodium butyrate applies to regulate breast cancer cell growth. Our results have shown that the percentage of viable cells was reduced following treatment with increasing concentration of sodium butyrate which is consistent with the effect of sodium butyrate on tongue (Li et al 2014), pancreas (Natoni et al 2005), and prostate (Paskova et al 2013). Accordingly, the sodium butyrate-induced cell death was significantly abrogated upon pretreatment with 15-Lox-1 inhibitor in MCF-7 and MDA-MB-468.…”

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

“…26 The gene-specific primers for human PKM2 and GAPDH were used as previously reported. 13,26 Relative mRNA expression was calculated as compared to GAPDH using comparative CT method.…”

“…16,26 Immunohistochemical staining for PKM2 was performed on 4-mm formalin-fixed, paraffin-embedded tumor specimens. Briefly, tissue sections from representative paraffin blocks were deparaffinised and rehydrated.…”

“…PKM2 immunoreactivity in both animal and human samples was semi-quantitatively evaluated on the basis of staining intensity and distribution using the immunoreactive score which was calculated as intensity score £ proportion score as we reported previously. 16,26 Intensity score was defined as 0, negative; 1, weak; 2, moderate; 3, strong, while the proportion score was graded as 0, negative; 1, <10%; 2,11-50%; 3,51-80%; 4,>80% positive cells. Thus, the total score ranged from 0-12.…”

RNA interference in head and neck oncology

“…Polycomb group proteins (PcG) are critical transcriptional repressors that epigenetically modify chromatin and contribute to cell fate, stem cell self-renewal and cancer development (52,53). B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) is the core member of the polycomb repressive complex 1 (PRC1), one of two PRCs in PcG (53).…”