YEATS2: a novel cancer epigenetic reader and potential therapeutic target.

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-04-26 DOI:10.1186/s12935-025-03797-9

Kangkang Ji, Guoping Chen, Yan Wang, Yunyi Li, Jian Chen, Mingqian Feng

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引用次数: 0

Abstract

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.

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YEATS2：一种新的癌症表观遗传解读器和潜在的治疗靶点。

YEATS2是一种进化保守的组蛋白酰化标记（H3K27ac, H3K27cr, H3K27bz）的读取器，在多种癌症（包括非小细胞肺癌（NSCLC），胰腺导管腺癌（PDAC）和肝细胞癌（HCC））中起着中心致癌驱动作用。其结构可塑性的YEATS结构域将酰基辅酶a代谢与染色质重塑连接起来，放大MYC、BCL2和PD-L1等存活基因的转录。YEATS2通过ATAC复合物募集维持NSCLC中的核糖体生物发生，在PDAC中增强NF-κ b依赖性免疫逃避，在HCC中激活PI3K/ akt驱动的代谢重布线。结构研究证明了一种独特的芳香笼结构，选择性地参与各种酰基化组蛋白。尽管基于吡唑吡啶的靶向YEATS结构域的抑制剂显示出临床前疗效，但开发同种异构体选择性药物仍然具有挑战性。临床上，YEATS2过表达与治疗耐药相关，并可能与免疫检查点阻断协同作用。这篇综述整合了YEATS2在表观遗传调控中的作用机制，评估了其治疗潜力，并提出了未来的方向：阐明全长复杂拓扑结构，绘制合成致死相互作用物，优化选择性抑制剂。破坏yeats2介导的表观遗传适应为精确的癌症治疗提供了新的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.