Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA; Department of Pharmacology, Weill Cornell Graduate School of Biomedical Sciences, New York, NY, USA.
Biochim Biophys Acta Mol Basis Dis. 2024 Jun;1870(5):167161. doi: 10.1016/j.bbadis.2024.167161. Epub 2024 Apr 9.
The tongue epithelium is maintained by a proliferative basal layer. This layer contains long-lived stem cells (SCs), which produce progeny cells that move up to the surface as they differentiate. B-lymphoma Mo-MLV insertion region 1 (BMI1), a protein in mammalian Polycomb Repressive Complex 1 (PRC1) and a biomarker of oral squamous cell carcinoma, is expressed in almost all basal epithelial SCs of the tongue, and single, Bmi1-labelled SCs give rise to cells in all epithelial layers. We previously developed a transgenic mouse model (KrTB) containing a doxycycline- (dox) controlled, Tet-responsive element system to selectively overexpress Bmi1 in the tongue basal epithelial SCs. Here, we used this model to assess BMI1 actions in tongue epithelia. Genome-wide transcriptomics revealed increased levels of transcripts involved in the cellular response to hypoxia in Bmi1-overexpressing (KrTB+DOX) oral epithelia even though these mice were not subjected to hypoxia conditions. Ectopic Bmi1 expression in tongue epithelia increased the levels of hypoxia inducible factor-1 alpha (HIF1α) and HIF1α targets linked to metabolic reprogramming during hypoxia. We used chromatin immunoprecipitation (ChIP) to demonstrate that Bmi1 associates with the promoters of HIF1A and HIF1A-activator RELA (p65) in tongue epithelia. We also detected increased SC proliferation and oxidative stress in Bmi1-overexpressing tongue epithelia. Finally, using a human oral keratinocyte line (OKF6-TERT1R), we showed that ectopic BMI1 overexpression decreases the oxygen consumption rate while increasing the extracellular acidification rate, indicative of elevated glycolysis. Thus, our data demonstrate that high BMI1 expression drives hypoxic signaling, including metabolic reprogramming, in normal oral cavity epithelia.
舌上皮由一个增殖的基底层维持。这个层含有长寿的干细胞（SCs），它们产生的祖细胞在分化过程中向上移动到表面。B 淋巴瘤 Mo-MLV 插入区 1（BMI1）是哺乳动物多梳抑制复合物 1（PRC1）中的一种蛋白，也是口腔鳞状细胞癌的生物标志物，在舌的几乎所有基底上皮 SC 中都有表达，而单个 Bmi1 标记的 SC 会产生所有上皮层的细胞。我们之前开发了一种含有强力霉素（dox）控制的 Tet 反应元件系统的转基因小鼠模型（KrTB），以选择性地在舌基底上皮 SC 中过表达 Bmi1。在这里，我们使用该模型来评估 BMI1 在舌上皮中的作用。全基因组转录组学显示，即使这些小鼠没有受到缺氧条件的影响，过表达 Bmi1 的（KrTB+DOX）口腔上皮中与细胞对缺氧反应相关的转录本水平升高。舌上皮中的异位 Bmi1 表达增加了缺氧诱导因子-1α（HIF1α）的水平，以及与缺氧时代谢重编程相关的 HIF1α 靶标。我们使用染色质免疫沉淀（ChIP）证明 Bmi1 与舌上皮中的 HIF1A 和 HIF1A-激活剂 RELA（p65）的启动子结合。我们还检测到过表达 Bmi1 的舌上皮中 SC 增殖和氧化应激增加。最后，使用人口腔角质形成细胞系（OKF6-TERT1R），我们表明异位 BMI1 过表达降低了耗氧率，同时增加了细胞外酸化率，表明糖酵解增加。因此，我们的数据表明，高 BMI1 表达驱动正常口腔上皮中的缺氧信号转导，包括代谢重编程。
