文章：

可靶向的MYBL2-ATAD2轴调控卵巢癌的细胞增殖

A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer 

原文发布日期：2022-09-23 

英文摘要：

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. 

摘要翻译： 

染色质修饰酶ATAD2在恶性肿瘤中赋予致癌能力与增殖优势。我们先前研究发现ATAD2是卵巢癌（OC）细胞增殖的标志物和驱动因子，但其调控机制及参与细胞增殖的具体机制尚不明确。本研究揭示ATAD2呈现典型的G2/M期基因特征，通过促进有丝分裂进程发挥作用。敲除ATAD2会导致有丝分裂阻滞，并降低卵巢癌细胞通过诺考达唑阻滞的有丝分裂的能力。ChIP-seq数据分析表明，DREAM和MYBL2-MuvB（MMB）这两种可切换的MuvB复合物可与ATAD2启动子中的CHR元件结合，这代表了G2/M期基因周期性调控的典型特征和核心机制。作为MYBL2的下游靶标，ATAD2缺失显著削弱了MYBL2驱动的细胞增殖。值得注意的是，ATAD2沉默还会反馈性导致MYBL2蛋白稳定性降低。在组织整体水平和单细胞水平上，MYBL2与ATAD2的显著共表达表明卵巢癌患者中存在MYBL2-ATAD2信号轴。该信号轴在肿瘤发生过程中被激活且与TP53突变相关，尤其在高级别浆液性癌和耐药性卵巢癌中呈现高度活化状态。通过CRISPR/Cas9介导的ATAD2敲除破坏该信号轴，可抑制皮下移植瘤模型中卵巢癌的体内生长；而使用ATAD2抑制剂靶向该信号轴，在药物敏感和耐药卵巢癌细胞中均显示出显著治疗效果。本研究不仅鉴定出新型MYBL2-ATAD2增殖信号轴，更凸显了其在开发新治疗策略（特别是针对高级别浆液性癌和耐药性卵巢癌）方面的潜在应用价值。

原文链接：

A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer