Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Cell Physiol. 2024 Mar;239(3):e31068. doi: 10.1002/jcp.31068. Epub 2023 Jun 25.
N6-methyladenosine (m A) is one of the main epitranscriptomic modifications that accelerates the progression of malignant tumors by modifying RNA. Methyltransferase-like 16 (METTL16) is a newly identified methyltransferase that has been found to play an important oncogenic role in a few malignancies; however, its function in osteosarcoma (OS) remains unclear. In this study, METTL16 was found to be upregulated in OS tissues, and associated with poor prognosis in OS patients. Functionally, METTL16 substantially promoted OS cell proliferation, migration, and invasion in vitro and OS growth in vivo. Mechanistically, vacuolar protein sorting protein 33b (VPS33B) was identified as the downstream target of METTL16, which induced m A modification of VPS33B and impaired the stability of the VPS33B transcript, thereby degrading VPS33B. In addition, VPS33B was found to be downregulated in OS tissues, VPS33B knockdown markedly attenuated shMETTL16-mediated inhibition on OS progression. Finally, METTL16/VPS33B might facilitate OS progression through PI3K/AKT pathway. In summary, this study revealed an important role for the METTL16-mediated m A modification in OS progression, implying it as a promising target for OS treatment.
N6-甲基腺苷（m6A）是一种主要的转录后修饰物，通过修饰 RNA 加速恶性肿瘤的进展。甲基转移酶样蛋白 16（METTL16）是一种新发现的甲基转移酶，已被发现在少数恶性肿瘤中发挥重要致癌作用；然而，其在骨肉瘤（OS）中的功能尚不清楚。在本研究中，发现 METTL16 在 OS 组织中上调，并与 OS 患者的不良预后相关。功能上，METTL16 显著促进了 OS 细胞的体外增殖、迁移和侵袭以及体内 OS 的生长。机制上，鉴定出液泡蛋白分选蛋白 33b（VPS33B）是 METTL16 的下游靶标，它诱导 VPS33B 的 m6A 修饰并破坏 VPS33B 转录本的稳定性，从而降解 VPS33B。此外，在 OS 组织中发现 VPS33B 下调，VPS33B 敲低显著减弱了 shMETTL16 介导的对 OS 进展的抑制作用。最后，METTL16/VPS33B 可能通过 PI3K/AKT 通路促进 OS 进展。总之，本研究揭示了 METTL16 介导的 m6A 修饰在 OS 进展中的重要作用，表明它是 OS 治疗的有前途的靶点。
