KAT8

本文为转化医学网原创，转载请注明出处 作者：Sophia 导读： 膀胱癌（BC）是最常见的肿瘤之一，其特征是复发率高且缺乏靶向治疗。 近日，中山大学武远众及康铁邦共同通讯在Advanced Science 在线发表题为“Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer”的研究论文， 我们的研究表明，YEATS4 翻译后修饰的失调可能是 BC 中 YEATS4 上调的主要原因。因此，通过靶向 KAT8/YEATS4 轴来抑制 YEATS4 乙酰化可能是 BC 患者的一种有前途的治疗干预措施。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202310146 研究背景 01 膀胱癌（BC）是全球最常见的恶性肿瘤之一。膀胱癌的发病率和死亡率逐年增加。尽管 BC 标本中基因突变（如 FGFR3 和 p53）的鉴定以及染色体改变揭示了 BC 的发展，但仍缺乏特异性的靶向治疗。基于顺铂 （DDP） 的联合化疗已成为侵袭性或转移性 BC 患者的重要辅助疗法。然而， 大多数 BC 患者会逐渐出现 DDP 耐药。因此，亟需确定BC的新治疗靶点。 含有 YEATS 结构域的蛋白质具有保守的 YEATS 结构域，具有重要的生物学意义，因为它们最近被确定为组蛋白乙酰化的新读者。在人类中，有 4 种含有 YEATS 结构域的蛋白质，包括 AF9、ENL、YEATS4 和 YEATS2。特别是，ENL与对急性白血病发展至关重要的癌基因的反式激活有关。 诱导 ENL 蛋白降解或靶向 ENL YEATS 结构域导致致癌基因的抑制和癌细胞活力的降低，表明 YEATS 蛋白可能是癌症治疗的潜在治疗靶点。 YEATS4，也称为 GAS41，最初被发现在胶质母细胞瘤中扩增。新兴研究表明，YEATS4 对细胞存活、细胞生长和 p53 通路调节至关重要。尽管意识到 YEATS4 在癌症中的关键作用， 但由于对 YEATS4 在癌症中如何调节知之甚少，这种蛋白质的靶向策略仍然不可用。 研究结果 02 本研究，我们使用 CRISPR-Cas9 文库筛选报告了含 YEATS 结构域的蛋白 4 （YEATS4） 是 BC 细胞活力的重要基因，并且 HUWE1 是一种 E3 连接酶，负责 YEATS4 泛素化和蛋白酶体降解通过蛋白质稳定性调节剂筛选测定。 KAT8介导的YEATS4乙酰化损害了其与HUWE1的相互作用，从而阻止了其泛素化和降解。YEATS4 和 KAT8 的蛋白水平呈正相关，这两种蛋白的高水平与 BC 患者的总生存期较差有关。重要的是，用 KAT8 抑制剂 MG149 抑制 YEATS4 乙酰化可降低 YEATS4 乙酰化，降低细胞活力，并使 BC 细胞对顺铂治疗敏感。 研究结果揭示了 KAT8/YEATS4 轴在 BC 细胞肿瘤生长和顺铂敏感性中的关键作用，有可能为 BC 患者提供一种新的治疗策略。 研究结论 03 在这项研究中，我们发现 KAT8/YEATS4 轴对 BC 至关重要。具体来说，在 BC 细胞中，KAT8 介导的 YEATS4 乙酰化位点 K64、65 和 69 通过阻断其 HUWE1 依赖性降解来促进 YEATS4 的稳定，这反过来又有助于 DNA 修复和肿瘤生长，从而导致 DDP 耐药性。MG149 抑制 KAT8 抑制 YEATS4 乙酰化，导致 HUWE1 与 YEATS4 结合增加，从而促进 HUWE1 介导的 YEATS4 泛素化和蛋白酶体降解，从而减少 DNA 修复和肿瘤生长并增强 DDP 敏感性（图 8）。 BC中KAT8/YEATS4轴功能的拟议模型。 KAT8 药物的 YEATS4 乙酰化位点 K64、65 和 69 阻断 HUWE1 与 YEATS4 的结合，从而促进 YEATS4 稳定，从而促进 DNA 修复和肿瘤生长。MG149 抑制 KAT8 抑制 YEATS4 乙酰化，导致 HUWE1 与 YEATS4 结合增加和蛋白酶体降解，从而增强基因组不稳定性并抑制 BC 细胞生长。MG149 阻断 YEATS4 乙酰化可增加 DDP 敏感性并加速 BC 细胞死亡。 参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202310146 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

引言膀胱癌（BC）是最常见的肿瘤之一，其特征是复发率高且缺乏靶向治疗方案。2024年3月25日，中山大学武远众及康铁邦共同通讯在Advanced Science 在线发表题为“Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer”的研究论文，该研究使用CRISPR-Cas9文库筛选报告了含YEATS结构域的蛋白4（YEATS4），这是BC细胞保持活性的重要基因。HUWE1是一种E3连接酶，蛋白质稳定性调节剂筛选试验发现其负责YEATS4泛素化和蛋白酶体降解。KAT8介导的YEATS4乙酰化损害了其与HUWE1的相互作用，从而阻止了其泛素化和降解。YEATS4和KAT8的蛋白水平呈正相关，而这两种蛋白的高水平与BC患者的总生存期密切相关。重要的是，KAT8抑制剂MG149抑制YEATS4乙酰化可降低YEATS4乙酰化，降低细胞活力，并使BC细胞对顺铂治疗敏感。该研究揭示了KAT8/YEATS4轴在BC细胞肿瘤生长和顺铂敏感性中的关键作用，有可能为BC患者提供一种新的治疗策略。膀胱癌（BC）是全球最常见的恶性肿瘤之一，发病率和死亡率逐年增加。尽管对BC标本中基因突变（如FGFR3、p53和染色体改变）的鉴定推动了BC治疗的发展，但仍然缺乏特异性靶向治疗方案。基于顺铂（DDP）的联合化疗已成为侵袭性或转移性BC患者的重要辅助治疗手段，但大多数BC患者会逐渐对DDP产生耐药性。因此，迫切需要为BC确定新的治疗靶点。由于具有保守的YEATS结构域，含YEATS结构域的蛋白质往往发挥重要的生物学作用，其最近被鉴定为组蛋白乙酰化的新型编码器。人类有4种含酵母结构域的蛋白质，包括AF9、ENL、YEATS4和YEATS2。特别是ENL与对急性白血病发展至关重要的癌基因的反式激活有关。诱导ENL蛋白降解或靶向ENLYEATS结构域将引发致癌基因的抑制和癌细胞活力的降低，表明YEATS蛋白可能是癌症治疗的潜在靶点。YEATS4 对膀胱癌细胞的生长至关重要（Credit: Advanced Science）YEATS4也被称为GAS41，最初在胶质母细胞瘤中发现其扩增趋势。新的研究表明，YEATS4对细胞存活、细胞生长和p53途径调节至关重要。尽管认识到YEATS4在癌症中的关键作用，但对YEATS4在癌症中的调控机制仍了解甚少，无法制定相应的蛋白靶向治疗策略。该研究证明了组蛋白乙酰转移酶KAT8对YEATS4的乙酰化削弱了其与E3连接酶HUWE1的结合，稳定YEATS4并促进BC肿瘤生长，靶向KAT8/YEATS4轴抑制肿瘤生长使BC细胞对顺铂敏感。原文链接https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202310146责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

A new study has identified 17 genetic variants that may influence Alzheimer's disease risk, putting researchers one step closer to uncovering biological pathways to target for future treatment and prevention. Identifying genetic variants and the role they play in predisposing people to Alzheimer's disease can help researchers better understand how to treat the neurodegenerative condition for which there is currently no cure. A new study led by Boston University School of Public Health (BUSPH) and UTHealth Houston School of Public Health has identified several genetic variants that may influence Alzheimer's disease risk, putting researchers one step closer to uncovering biological pathways to target for future treatment and prevention. Published in the journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association, the study utilized whole genome sequencing and identified 17 significant variants associated with Alzheimer's disease in five genomic regions. This data enables researchers to pinpoint rare and important genes and variants, building upon genome-wide association studies, which focus only on common variants and regions. The findings underscore the value of whole genome sequencing data in gaining long-sought insight into the ultimate causes and risk factors for Alzheimer's disease, which is the fifth leading cause of death among people 65 and older in the United States. As the most common form of dementia, Alzheimer's disease currently affects more than 6 million Americans and that number is expected to skyrocket to nearly13 million by 2050. "Prior genome-wide association studies using common variants have identified regions of the genome, and sometimes genes, that are associated with Alzheimer's disease," says study co-senior author Dr. Anita DeStefano, professor of biostatistics at BUSPH. "Whole genome sequence data interrogates every base pair in the human genome and can provide more information about which specific genetic change in a region may be contributing to Alzheimer's disease risk or protection." For the study, the researchers conducted single variant association analyses and rare variant aggregation association tests using whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), a genetics initiative that the National Institutes of Health developed in 2012 as part of the National Alzheimer's Project Act's goal to treat and prevent the disease. The ADSP data include more than 95 million variants among 4,567 participants with or without the disease. Among the 17 significant variants that were linked to Alzheimer's disease, the KAT8 variant was one of the most notable, as it was associated with the disease in both the single and rare variant analyses. The researchers also found associations with several rare TREM2 variants. "By using whole genome sequencing in a diverse sample, we were able to not only identify novel genetic variants associated with Alzheimer's disease risk in known genetic regions, but also characterize whether the known and novel associations are shared across populations," says study co-lead and corresponding author Dr. Chloé Sarnowski, assistant professor in the Department of Epidemiology at UTHealth Houston School of Public Health. The ADSP includes ethnically diverse participants, and the population-specific assessments focused on White/European-ancestry, Black/African-American, and Hispanic/Latino subgroups, as well as a multi-population meta-analysis. Historically, Black and and Latino populations have been underrepresented in genetic studies of Alzheimer's disease despite having a higher prevalence of the disease than other ethnic groups. "Including participants that represent diverse genetic ancestry and diverse environments in terms of social determinants of health is important to understanding the full spectrum of Alzheimer's disease risk, as both the prevalence of the disease and the frequencies of genetic variants can differ among populations," says Dr. DeStefano. The sample sizes in the population-specific analyses were small, so the team had limited ability to detect associations, she says, "but we replicated known population differences for the APOE gene, which is one of the best-known and strongest risk genes for Alzheimer's disease." In future studies, the researchers hope to examine the population-specific variants they identified in much larger sample sizes, as well as explore how these variants affect biological functioning. "We are currently working on expanding this research to be able to use whole genome sequencing with larger sample sizes in the ADSP to be able to look at the full array of genetic variants, not only within known Alzheimer's disease genetic regions, but across the whole genome," says co-senior author Dr. Gina Peloso, associate professor of biostatistics at BUSPH. The study was also co-led by Yanbing Wang while she was a PhD student in biostatistics at BUSPH. It was funded by the National Institute on Aging under Award Numbers U01 AG058589 and U01 AG068221.