<br>E2F8 通过转录激活 RRM2 发挥促癌作用，E2F8 敲除与 WEE1 抑制协同抑制肺腺癌,BIOCHEMICAL PHARMACOLOGY

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E2F8 通过转录激活 RRM2 发挥促癌作用，E2F8 敲除与 WEE1 抑制协同抑制肺腺癌
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2023-10-19 , DOI: 10.1016/j.bcp.2023.115854
Kaiping Liu ₁ , Ling Wang ₂ , Zhiyuan Lou ₂ , Lijuan Guo ₂ , Yuanling Xu ₂ , Hongyan Qi ₂ , Zejun Fang ₃ , Lingming Mei ₃ , Xiang Chen ₃ , Xiaomin Zhang ₃ , Jimin Shao ₄ , Xueping Xiang ₂

Affiliation

核糖核苷酸还原酶（RR）是一种限速酶，通过将核苷酸二磷酸（NDP）还原为脱氧核糖核苷酸二磷酸（dNDP）来促进 DNA 复制和修复，因此对细胞增殖和癌症发展至关重要。转录因子的 E2F 家族包括参与细胞周期控制的基因表达的关键调节因子。在本研究中，E2F8 在肺腺癌（LUAD）患者的大多数癌组织中表达显著增加，并通过数据库和临床样本分析与 RRM2 的表达相关。E2F8 和 RRM2 蛋白表达与肿瘤-淋巴结转移（TNM）病理分期呈正相关，E2F8 和 RRM2 高表达预示着 LUAD 患者 5 年总生存率较低。过表达和敲低实验表明，E2F8 对 LUAD 细胞增殖、DNA 合成和细胞周期进程至关重要，这些都是 RRM2 依赖性的。报告基因、ChIP-qPCR 和 DNA pulldown-Western blot 检测表明，E2F8 通过直接与 LUAD 细胞中的 RRM2 启动子结合来激活 RRM2 基因的转录。既往研究表明，抑制 WEE1 激酶可以抑制 CDK1/2 的磷酸化并促进 RRM2 的降解。我们在这里进一步表明，E2F8 敲低与 MK-1775（一种正在临床试验中评估的 WEE1 抑制剂）的组合在体外和体内协同抑制了 LUAD 细胞的增殖并促进了细胞凋亡。因此，本研究揭示了 E2F8 作为原癌转录激活剂的新作用，通过激活 LUAD 中的 RRM2 表达，靶向 RRM2 的转录和降解机制除了常规抑制 RR 酶活性外，还可以对 LUAD 治疗产生协同抑制作用。

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E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma

Ribonucleotide reductase (RR) is a rate-limiting enzyme that facilitates DNA replication and repair by reducing nucleotide diphosphates (NDPs) to deoxyribonucleotide diphosphates (dNDPs) and is thereby crucial for cell proliferation and cancer development. The E2F family of transcription factors includes key regulators of gene expression involved in cell cycle control. In this study, E2F8 expression was significantly increased in most cancer tissues of lung adenocarcinoma (LUAD) patients and was correlated with the expression of RRM2 through database and clinical samples analysis. The protein expression of E2F8 and RRM2 were positively correlated with tumor–node–metastasis (TNM) pathological stage, and high expression of E2F8 and RRM2 predicted a low 5-year overall survival rate in LUAD patients. Overexpression and knockdown experiments showed that E2F8 was essential for LUAD cell proliferation, DNA synthesis, and cell cycle progression, which were RRM2-dependent. Reporter gene, ChIP-qPCR, and DNA pulldown–Western blot assays indicated that E2F8 activated the transcription of the RRM2 gene by directly binding with the RRM2 promoter in LUAD cells. Previous studies indicated that inhibition of WEE1 kinase can suppress the phosphorylation of CDK1/2 and promote the degradation of RRM2. We further showed here that the combination of E2F8 knockdown with MK-1775, an inhibitor of WEE1 being evaluated in clinical trials, synergistically suppressed proliferation and promoted apoptosis of LUAD cells in vitro and in vivo. Thus, this study reveals a novel role of E2F8 as a proto-oncogenic transcription activator by activating RRM2 expression in LUAD, and targeting both the transcription and degradation mechanisms of RRM2 could produce a synergistic inhibitory effect for LUAD treatment in addition to conventional inhibition of RR enzyme activity.

更新日期：2023-10-19

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