靶向转录因子 YY1 与组蛋白去甲基化酶 KDM5C 的缺失是合成致死的。

IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-10-21 DOI:10.1038/s44319-024-00290-8
Qian Zheng, Pengfei Li, Yulong Qiang, Jiachen Fan, Yuzhu Xing, Ying Zhang, Fan Yang, Feng Li, Jie Xiong
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引用次数: 0

摘要

了解表观遗传修饰因子的酶和支架功能对于开发癌症表观遗传疗法非常重要。H3K4me2/3组蛋白去甲基化酶KDM5C已被证明能调节转录。KDM5C 的多种作用可能是由其相互作用伙伴决定的,而这些伙伴在很大程度上还不为人所知。在这项研究中,我们筛选了 KDM5C 结合蛋白,结果表明 YY1 与 KDM5C 有相互作用。当KDM5C和YY1都被耗尽时,会产生协同抗肿瘤效应,而靶向YY1似乎是KDM5C缺陷癌细胞的一个弱点。从机理上讲,KDM5C 可促进 YY1 染色质的全局招募,尤其是在启动子处。此外,KDM5C介导的YY1染色质结合需要完整的KDM5C JmjC结构域,而非KDM5C组蛋白去甲基化酶活性。转录谱分析显示,KDM5C 和 YY1 的双重抑制增加了细胞周期和细胞凋亡相关基因的转录抑制。总之,我们的工作证明了 YY1 和 KDM5C 之间的合成致死相互作用,并提出了癌症治疗的组合疗法。
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Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C.

An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.

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来源期刊
EMBO Reports
EMBO Reports 生物-生化与分子生物学
CiteScore
11.20
自引率
1.30%
发文量
267
审稿时长
1 months
期刊介绍: EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry. 
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