CEINGE-Advanced Biotechnologies "Franco Salvatore", Napoli, Italy.
Department of Molecular Medicine and Medical Biotechnologies, University of Napoli "Federico II", Napoli, Italy.
Cell Death Dis. 2023 Sep 27;14(9):638. doi: 10.1038/s41419-023-06167-3.
Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas. The small molecule SETD8 inhibitor UNC0379, as well as siRNA-mediated inhibition of SETD8, blocked glioblastoma cell proliferation, by inducing DNA damage and activating cell cycle checkpoints. Specifically, in p53-proficient glioblastoma cells, SETD8 inhibition and DNA damage induced p21 accumulation and G1/S arrest whereas, in p53-deficient glioblastoma cells, DNA damage induced by SETD8 inhibition resulted in G2/M arrest mediated by Chk1 activation. Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment.
尽管研究力度很大，但胶质母细胞瘤仍然是一种无法治愈的脑肿瘤，中位生存时间只有 15 个月。因此，寻找新的治疗靶点迫在眉睫。本研究显示，赖氨酸甲基转移酶 SETD8 在 50%的高级别神经胶质瘤中过度表达。小分子 SETD8 抑制剂 UNC0379 以及通过 siRNA 介导的 SETD8 抑制作用，通过诱导 DNA 损伤和激活细胞周期检查点来阻断神经胶质瘤细胞增殖。具体而言，在 p53 功能正常的神经胶质瘤细胞中，SETD8 抑制和 DNA 损伤诱导了 p21 的积累和 G1/S 期阻滞，而在 p53 缺陷的神经胶质瘤细胞中，SETD8 抑制诱导的 DNA 损伤导致 Chk1 激活介导的 G2/M 期阻滞。通过 Wee1 激酶抑制剂adavosertib 阻断检查点，使 UNC0379 诱导的神经胶质瘤细胞系和原代细胞发生 DNA 损伤，进入有丝分裂，然后通过有丝分裂灾难而死亡。最后，UNC0379 和 adavosertib 在抑制小鼠异种移植模型中的神经胶质瘤生长方面具有协同作用，为进一步探索这种新的药理学方法辅助治疗神经胶质瘤提供了强有力的依据。
