A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer
A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer
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DOI：
10.1038/s41417-022-00538-2
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发表时间：
2022-09-23
影响因子：
6.4
通讯作者：
Liu, Jian
中科院分区：
文献类型：
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作者：
Liu, Qun;Liu, Heshu;Liu, Jian
染色质修饰酶ATAD2在恶性肿瘤中具有致癌活性和增殖优势。我们以前发现ATAD2是卵巢癌(OC)细胞增殖的标志物和驱动力；然而，ATAD2调控和参与细胞增殖的机制仍然不清楚。在这里，我们揭示了ATAD2表现出经典的G2/M基因特征，其功能是促进有丝分裂的进行。ATAD2消融导致有丝分裂停滞，并降低OC细胞通过诺康唑抑制的有丝分裂的能力。CHIP-SEQ数据分析表明，DREAM和MYBL2-MuvB(MMB)这两个可切换的MuvB复合体结合了ATAD2启动子中的CHR元件，代表了G2/M基因周期调控的典型特征和主要机制。作为MYBL2的下游靶点，ATAD2的缺失显著抑制了MYBL2诱导的细胞增殖。有趣的是，ATAD2沉默也反馈到破坏MYBL2蛋白的稳定。MYBL2和ATAD2在整体组织和单细胞水平的显著共同表达表明，在OC患者中存在MYBL2-ATAD2信号。这种信号在肿瘤发生过程中被激活，并与TP53突变相关，尤其是在高级别浆液性和耐药的OCS中发现其过度激活。在皮下移植瘤小鼠模型中，通过CRISPR/Cas9介导的ATAD2消融来干扰这一信号转导抑制了OC的体内生长，而ATAD2抑制剂靶向该信号转导的药物在药物敏感和耐药的OC细胞中都显示出很高的治疗效果。总之，我们确定了一个新的MYBL2-ATAD2增殖信号轴，并强调了它在开发新的治疗策略方面的潜在应用，特别是对高级别浆液性和耐药的OCS。
The chromatin-modifying enzyme ATAD2 confers oncogenic competence and proliferative advantage in malignances. We previously identified ATAD2 as a marker and driver of cell proliferation in ovarian cancer (OC); however, the mechanisms whereby ATAD2 is regulated and involved in cell proliferation are still unclear. Here, we disclose that ATAD2 displays a classical G2/M gene signature, functioning to facilitate mitotic progression. ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. ChIP-seq data analyses demonstrated that DREAM and MYBL2-MuvB (MMB), two switchable MuvB-based complexes, bind the CHR elements in the ATAD2 promoter, representing a typical feature and principle mechanism of the periodic regulation of G2/M genes. As a downstream target of MYBL2, ATAD2 deletion significantly impaired MYBL2-driven cell proliferation. Intriguingly, ATAD2 silencing also fed back to destabilize the MYBL2 protein. The significant coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels highlights the existence of the MYBL2-ATAD2 signaling in OC patients. This signaling is activated during tumorigenesis and correlated with TP53 mutation, and its hyperactivation was found especially in high-grade serous and drug-resistant OCs. Disrupting this signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model, while pharmacologically targeting this signaling with an ATAD2 inhibitor demonstrated high therapeutic efficacy in both drug-sensitive and drug-resistant OC cells. Collectively, we identified a novel MYBL2-ATAD2 proliferative signaling axis and highlighted its potential application in developing new therapeutic strategies, especially for high-grade serous and drug-resistant OCs.