Ji Kangkang, Chen Guoping, Wang Yan, Li Yunyi, Chen Jian, Feng Mingqian
College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Department of Clinical Medical Research, Binhai County People's Hospital, Clinical Medical College of Yangzhou University, Yancheng, 224500, Jiangsu, China.
Cancer Cell Int. 2025 Apr 26;25(1):162. doi: 10.1186/s12935-025-03797-9.
YEATS2, an evolutionarily conserved reader of histone acylation marks (H3K27ac, H3K27cr, H3K27bz), functions as a central oncogenic driver in diverse cancers, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Its structurally plastic YEATS domain bridges acyl-CoA metabolism to chromatin remodeling, amplifying transcription of survival genes such as MYC, BCL2, and PD-L1. YEATS2 orchestrates malignancy-specific programs-sustaining ribosome biogenesis in NSCLC through ATAC complex recruitment, enhancing NF-κB-dependent immune evasion in PDAC, and activating PI3K/AKT-driven metabolic rewiring in HCC. Structural studies demonstrate a unique aromatic cage architecture that selectively engages diverse acylated histones. Although pyrazolopyridine-based inhibitors targeting the YEATS domain show preclinical efficacy, developing isoform-selective agents remains challenging. Clinically, YEATS2 overexpression correlates with therapy resistance and may synergize with immune checkpoint blockade. This review integrates mechanistic insights into the role of YEATS2 in epigenetic regulation, evaluates its therapeutic potential, and proposes future directions: elucidating full-length complex topologies, mapping synthetic lethal interactors, and optimizing selective inhibitors. Disrupting YEATS2-mediated epigenetic adaptation presents novel opportunities for precision cancer therapy.
YEATS2是一种对组蛋白酰化标记（H3K27ac、H3K27cr、H3K27bz）具有进化保守性的识别蛋白，在多种癌症中作为核心致癌驱动因子发挥作用，包括非小细胞肺癌（NSCLC）、胰腺导管腺癌（PDAC）和肝细胞癌（HCC）。其结构可塑性强的YEATS结构域将酰基辅酶A代谢与染色质重塑联系起来，增强了MYC、BCL2和PD-L1等生存基因的转录。YEATS2协调恶性肿瘤特异性程序——通过募集ATAC复合物维持NSCLC中的核糖体生物发生，增强PDAC中NF-κB依赖性免疫逃逸，并激活HCC中PI3K/AKT驱动的代谢重编程。结构研究表明其具有独特的芳香笼结构，可选择性结合多种酰化组蛋白。尽管基于吡唑并吡啶的靶向YEATS结构域的抑制剂显示出临床前疗效，但开发亚型选择性药物仍然具有挑战性。在临床上，YEATS2过表达与治疗耐药相关，并且可能与免疫检查点阻断协同作用。本综述整合了对YEATS2在表观遗传调控中作用的机制性见解，评估了其治疗潜力，并提出了未来的方向：阐明全长复合物拓扑结构、绘制合成致死相互作用蛋白图谱以及优化选择性抑制剂。破坏YEATS2介导的表观遗传适应性为精准癌症治疗带来了新的机遇。
