title: 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 CD44(+)CD133(+) 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.
authors.affiliation: 1] Head Neck Cancer Center, Institute of Stomatology, Nanjing Medical University, Jiangsu, China [2] Jiangsu Key Laboratory of Oral Disease, Nanjing, China.
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1] Head Neck Cancer Center, Institute of Stomatology, Nanjing Medical University, Jiangsu, China [2] Jiangsu Key Laboratory of Oral Disease, Nanjing, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Head Neck Cancer Center, Institute of Stomatology, Nanjing Medical University, Jiangsu, China.
authors.forename: Chunping
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Oral Pathology, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Oral Pathology, Nanjing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Qi
authors.affiliation: Department of Oral and Maxillofacial Surgery Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China.
authors.forename: Heming
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Oral and Maxillofacial Surgery Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China.
authors.forename: Jinhai
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Oral and Maxillofacial Surgery Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Oral and Maxillofacial Surgery Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Yang
authors.affiliation: 1] Head Neck Cancer Center, Institute of Stomatology, Nanjing Medical University, Jiangsu, China [2] Department of Oral and Maxillofacial Surgery Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008875:Middle Aged; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C069077:BMI1 protein, human; D056572:Histone Deacetylase Inhibitors; D019394:Ki-67 Antigen; D034741:RNA, Small Interfering; D063150:Polycomb Repressive Complex 1; D002945:Cisplatin