Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China.
Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China.
Cell Biol Toxicol. 2023 Dec;39(6):2841-2860. doi: 10.1007/s10565-023-09805-w. Epub 2023 Apr 14.
Glioblastoma (GBM) is a primary tumor in the intracranial compartment. Vasculogenic mimicry (VM) is a process in which a pipeline of tumor cells that provide blood support to carcinogenic cells is formed, and studying VM could provide a new strategy for clinical targeted treatment of GBM. In the present study, we found that SNORD17 and ZNF384 were significantly upregulated and promoted VM in GBM, whereas KAT6B was downregulated and inhibited VM in GBM. RTL-P assays were performed to verify the 2'-O-methylation of KAT6B by SNORD17; IP assays were used to detect the acetylation of ZNF384 by KAT6B. In addition, the binding of ZNF384 to the promoter regions of VEGFR2 and VE-cadherin promoted transcription, as validated by chromatin immunoprecipitation and luciferase reporter assays. And finally, knockdown of SNORD17 and ZNF384 combined with KAT6B overexpression effectively reduced the xenograft tumor size, prolonged the survival time of nude mice and reduced the number of VM channels. This study reveals a novel mechanism of the SNORD17/KAT6B/ZNF384 axis in modulating VM development in GBM that may provide a new goal for the comprehensive treatment of GBM.
胶质母细胞瘤（GBM）是颅内原发性肿瘤。血管生成拟态（VM）是肿瘤细胞形成管道为致癌细胞提供血液支持的过程，研究 VM 可为 GBM 的临床靶向治疗提供新策略。本研究发现，SNORD17 和 ZNF384 显著上调并促进 GBM 中的 VM，而 KAT6B 下调并抑制 GBM 中的 VM。RTL-P 检测用于验证 SNORD17 对 KAT6B 的 2'-O-甲基化；IP 检测用于检测 KAT6B 对 ZNF384 的乙酰化。此外，染色质免疫沉淀和荧光素酶报告基因检测证实 ZNF384 与 VEGFR2 和 VE-cadherin 启动子区域的结合促进转录。最后，SNORD17 和 ZNF384 的敲低与 KAT6B 的过表达相结合，有效降低了异种移植肿瘤的大小，延长了裸鼠的存活时间，并减少了 VM 通道的数量。本研究揭示了 SNORD17/KAT6B/ZNF384 轴在调节 GBM 中 VM 发育中的新机制，可能为 GBM 的综合治疗提供新的目标。
