Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1
Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1
复制标题
通过 TCP 和 GSK-J1 协同抑制 LSD1 和 JMJD3 治疗头颈鳞状细胞癌
DOI：
10.1038/s41416-019-0680-6
复制
发表时间：
2020-02-01
影响因子：
8.8
通讯作者：
Wang, Yanling
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Cheng, Jie;Wang, Yanling
背景组蛋白去甲基化酶LSD 1是一种重要的促肿瘤发生的介导因子，具有潜在的治疗靶点。然而，单独用LSD 1抑制剂治疗未能导致完全的癌症region. MethodsTCP（LSD 1抑制剂）和GSK-J1（JMJD 3抑制剂）对HNSCC的协同作用，测定在体外和临床前动物模型。通过RNA-seq鉴定HNSCC细胞中由化学试剂或siRNA调控的基因，并通过生物信息学方法进一步功能性询问。结果TCP和GSK-J1在体外可抑制细胞增殖，诱导细胞凋亡和衰老，而LSD 1和JMJD 3的同时敲低可在很大程度上再现TCP和GSK-J1的作用。联合治疗抑制体内肿瘤生长和进展。TCP和GSK-J1调节的差异表达基因在细胞增殖、凋亡和肿瘤相关通路中显著富集。SPP 1被鉴定为TCP和GSK-J1赋予的促凋亡作用的协同作用的介体。LSD 1和JMJD 3的共同上调与HNSCC.ConclusionsOur研究结果显示了一种新的治疗策略，同时LSD 1和JMJD 3抑制HNSCC患者的预后较差。
BackgroundThe histone demethylase LSD1 is a key mediator driving tumorigenesis, which holds potential as a promising therapeutic target. However, treatment with LSD1 inhibitors alone failed to result in complete cancer regression.MethodsThe synergistic effects of TCP (a LSD1 inhibitor) and GSK-J1 (a JMJD3 inhibitor) against HNSCC were determined in vitro and in preclinical animal models. Genes modulated by chemical agents or siRNAs in HNSCC cells were identified by RNA-seq and further functionally interrogated by bioinformatics approach. Integrative siRNA-mediated gene knockdown, rescue experiment and ChIP-qPCR assays were utilised to characterise the mediators underlying the therapeutic effects conferred by TCP and GSK-J1.ResultsTreatment with TCP and GSK-J1 impaired cell proliferation, induced apoptosis and senescence in vitro, which were largely recapitulated by simultaneous LSD1 and JMJD3 knockdown. Combinational treatment inhibited tumour growth and progression in vivo. Differentially expressed genes modulated by TCP and GSK-J1 were significantly enriched in cell proliferation, apoptosis and cancer-related pathways. SPP1 was identified as the mediator of synergy underlying the pro-apoptosis effects conferred by TCP and GSK-J1. Co-upregulation of LSD1 and JMJD3 associated with worse prognosis in patients with HNSCC.ConclusionsOur findings revealed a novel therapeutic strategy of simultaneous LSD1 and JMJD3 inhibition against HNSCC.