Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, 250012, China.
Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250013, P. R. China.
Cell Death Dis. 2023 Aug 8;14(8):510. doi: 10.1038/s41419-023-06024-3.
Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the mouth, characterised by rapid progression and poor prognosis. Hence, an urgent need exists for the development of predictive targets for early diagnosis, prognosis determination, and clinical therapy. Dysregulation of lymphoid enhancer-binding factor 1 (LEF1), an important transcription factor involved in the Wnt-β-catenin pathway, contributes to the poor prognosis of OSCC. Herein, we aimed to explore the correlation between LEF1 and histone lysine demethylase 4 A (KDM4A). Results show that the KDM4A complex is recruited by LEF1 and specifically binds the LATS2 promoter region, thereby inhibiting its expression, and consequently promoting cell proliferation and impeding apoptosis in OSCC. We also established NOD/SCID mouse xenograft models using CAL-27 cells to conduct an in vivo analysis of the roles of LEF1 and KDM4A in tumour growth, and our findings show that cells stably suppressing LEF1 or KDM4A have markedly decreased tumour-initiating capacity. Overall, the results of this study demonstrate that LEF1 plays a pivotal role in OSCC development and has potential to serve as a target for early diagnosis and treatment of OSCC.
口腔鳞状细胞癌（OSCC）是口腔最常见的癌症，其特点是进展迅速且预后不良。因此，迫切需要开发预测靶点，以实现早期诊断、预后判断和临床治疗。淋巴增强因子结合因子 1（LEF1）是 Wnt-β-连环蛋白通路中的一个重要转录因子，其失调导致 OSCC 的预后不良。在此，我们旨在探讨 LEF1 与组蛋白赖氨酸去甲基化酶 4A（KDM4A）之间的相关性。结果表明，LEF1 募集 KDM4A 复合物，并特异性结合 LATS2 启动子区域，从而抑制其表达，进而促进 OSCC 中的细胞增殖并阻碍细胞凋亡。我们还使用 CAL-27 细胞建立了 NOD/SCID 小鼠异种移植模型，以进行 LEF1 和 KDM4A 在肿瘤生长中的作用的体内分析，我们的研究结果表明，稳定抑制 LEF1 或 KDM4A 的细胞的肿瘤起始能力明显降低。总体而言，这项研究的结果表明，LEF1 在 OSCC 发展中起关键作用，并有可能成为 OSCC 早期诊断和治疗的靶点。
