Jiang Renbing, Dai Zhibing, Wu Junshen, Ji Suzhi, Sun Yachao, Yang Wenpeng
Department of Bone and Soft Tissue, Affiliated Tumor Hospital of Xinjiang Medical University, 830011, Urumqi, Xinjiang, China.
Cell Death Discov. 2022 Apr 8;8(1):179. doi: 10.1038/s41420-022-00926-5.
Osteosarcoma (OS) is a prevalent primary bone sarcoma. Methyltransferase-like 3 (METTL3) is dysregulated in human malignancies. This study explored the mechanism of METTL3 in OS cell proliferation. Our results demonstrated that METTL3 was highly expressed in OS, and correlated with the tumor size, clinical stage, and distant metastasis of OS patients. Higher METTL3 expression indicated poorer prognosis. METTL3 silencing inhibited the malignant proliferation of OS cells, while METTL3 overexpression led to an opposite trend. METTL3 upregulated histone deacetylase 5 (HDAC5) expression in OS cells by increasing the mA level. HDAC5 reduced the enrichment of H3K9/K14ac on miR-142 promoter, thus suppressing miR-142-5p expression and upregulating armadillo-repeat-containing 8 (ARMC8) level. HDAC5 overexpression or miR-142-5p silencing attenuated the inhibitory effect of METTL3 silencing on OS cell proliferation. Xenograft tumor experiment in nude mice confirmed that METTL3 silencing repressed OS cell proliferation in vivo via the HDAC5/miR-142-5p/ARMC8 axis. Collectively, METTL3-mediated mA modification facilitated OS cell proliferation via the HDAC5/miR-142-5p/ARMC8 axis.
骨肉瘤（OS）是一种常见的原发性骨肉瘤。甲基转移酶样3（METTL3）在人类恶性肿瘤中表达失调。本研究探讨了METTL3在OS细胞增殖中的作用机制。我们的结果表明，METTL3在OS中高表达，且与OS患者的肿瘤大小、临床分期及远处转移相关。METTL3表达越高，预后越差。METTL3沉默抑制了OS细胞的恶性增殖，而METTL3过表达则导致相反的趋势。METTL3通过提高mA水平上调OS细胞中组蛋白去乙酰化酶5（HDAC5）的表达。HDAC5减少了miR-142启动子上H3K9/K14ac的富集，从而抑制miR-142-5p的表达并上调含犰狳重复序列8（ARMC8）的水平。HDAC5过表达或miR-142-5p沉默减弱了METTL3沉默对OS细胞增殖的抑制作用。裸鼠异种移植瘤实验证实，METTL3沉默通过HDAC5/miR-142-5p/ARMC8轴在体内抑制OS细胞增殖。总之，METTL3介导的mA修饰通过HDAC5/miR-142-5p/ARMC8轴促进OS细胞增殖。
