Wang Xinmiao, Li Rui, Wu Luping, Chen Yang, Liu Shaopeng, Zhao Hui, Wang Yifan, Wang Lin, Shao Zhe
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education (KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, 430089, China.
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cell Biosci. 2022 Apr 27;12(1):49. doi: 10.1186/s13578-022-00785-8.
Epigenetic reprogramming is involved in multiple steps of human cancer evolution and is mediated by a variety of chromatin-modifying enzymes. Specifically, the histone lysine methyltransferase KMT2D is among the most frequently mutated genes in oral squamous cell carcinoma (OSCC). However, the mechanisms by which KMT2D affects the development of OSCC remain unclear.
In the present study, we found that the expression of KMT2D was elevated in OSCC compared to paracancerous specimens and was correlated with a more advanced tumor grade. More importantly, knockdown of KMT2D impaired their reconstitution in patient-derived organoids and decreased the expression of CD133 and β-catenin in OSCC cells. In in vitro and in vivo models, knockdown of KMT2D reduced the colony formation, migration and invasion abilities of OSCC cells and delayed tumor growth. Mechanistically, the dual-luciferase reporter and co-immunoprecipitation assays in two individual OSCC cell lines indicated that KMT2D may cooperate with MEF2A to promote the transcription activity of CTNNB1, thereby enhancing WNT signaling.
The upregulation of KMT2D contributes to stem-like properties in OSCC cells by sustaining the MEF2A-mediated transcriptional activity of CTNNB1.
表观遗传重编程参与人类癌症演变的多个步骤，并由多种染色质修饰酶介导。具体而言，组蛋白赖氨酸甲基转移酶KMT2D是口腔鳞状细胞癌（OSCC）中最常发生突变的基因之一。然而，KMT2D影响OSCC发生发展的机制仍不清楚。
在本研究中，我们发现与癌旁组织相比，KMT2D在OSCC中的表达升高，且与更高的肿瘤分级相关。更重要的是，敲低KMT2D会损害其在患者来源的类器官中的重建，并降低OSCC细胞中CD133和β-连环蛋白的表达。在体外和体内模型中，敲低KMT2D会降低OSCC细胞的集落形成、迁移和侵袭能力，并延缓肿瘤生长。机制上，在两个独立的OSCC细胞系中进行的双荧光素酶报告基因和免疫共沉淀试验表明，KMT2D可能与MEF2A协同作用，促进CTNNB1的转录活性，从而增强WNT信号传导。
KMT2D的上调通过维持MEF2A介导的CTNNB1转录活性，促进OSCC细胞的干细胞样特性。
