Department of Pharmacology, Soochow University, Suzhou, 215123, China.
Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, 215100, China.
Acta Pharmacol Sin. 2021 Aug;42(8):1338-1346. doi: 10.1038/s41401-020-00551-x. Epub 2020 Nov 12.
Recent studies show that the expression of CCND1, a key factor in cell cycle control, is increased following the progress and deteriotation of glioma and predicts poor outcomes. On the other hand, dysregulated deubiquitinase USP10 also predicts poor prognosis for patients with glioblastoma (GBM). In the present study, we investigated the interplay between CCND1 protein and USP10 in GBM cells. We showed that the expression of CCND1 was significantly higher in both GBM tissues and GBM-derived stem cells. USP10 interacted with CCND1 and prevented its K48- but not K63-linked polyubiquitination in GBM U251 and HS683 cells, which led to increased CCND1 stability. Consistent with the action of USP10 on CCND1, knockdown of USP10 by single-guided RNA downregulated CCND1 and caused GBM cell cycle arrest at the G1 phase and induced GBM cell apoptosis. To implement this finding in the treatment of GBMs, we screened a natural product library and found that acevaltrate (AVT), an active component derived from the herbal plant Valeriana jatamansi Jones was strikingly potent to induce GBM cell apoptosis, which was confirmed by the Annexin V staining and activation of the apoptotic signals. Furthermore, we revealed that AVT concentration-dependently suppressed USP10-mediated deubiquitination on CCND1 therefore inducing CCND1 protein degradation. Collectively, the present study demonstrates that the USP10/CCND1 axis could be a promising therapeutic target for patients with GBMs.
最近的研究表明，细胞周期调控关键因子 CCND1 的表达在神经胶质瘤的进展和恶化后增加，并预测预后不良。另一方面，失调的去泛素化酶 USP10 也预测胶质母细胞瘤（GBM）患者的预后不良。在本研究中，我们研究了 CCND1 蛋白和 USP10 在 GBM 细胞中的相互作用。我们表明，CCND1 的表达在 GBM 组织和 GBM 衍生的干细胞中均显著升高。USP10 与 CCND1 相互作用，并防止其在 GBM U251 和 HS683 细胞中发生 K48-而非 K63 连接的多泛素化，从而导致 CCND1 稳定性增加。与 USP10 对 CCND1 的作用一致，通过单导向 RNA 敲低 USP10 下调了 CCND1，并导致 GBM 细胞周期停滞在 G1 期，并诱导 GBM 细胞凋亡。为了将这一发现应用于 GBM 的治疗，我们筛选了天然产物文库，发现乙酰缬草酯（AVT），一种源自草药缬草（Valeriana jatamansi Jones）的活性成分，对诱导 GBM 细胞凋亡具有显著的作用，这通过 Annexin V 染色和凋亡信号的激活得到了证实。此外，我们揭示了 AVT 浓度依赖性地抑制 USP10 介导的 CCND1 去泛素化，从而诱导 CCND1 蛋白降解。综上所述，本研究表明 USP10/CCND1 轴可能是 GBM 患者有前途的治疗靶点。
