H4K79和H4K91组蛋白乳酸化,新发现的乳腺癌中富集的乳酸化位点。

IF 12.8 1区 医学 Q1 ONCOLOGY
Jiena Liu, Liuying Zhao, Meisi Yan, Shengye Jin, Lingmin Shang, Jianyu Wang, Qin Wang, Shilu Zhao, Zibo Shen, Tong Liu, Hao Wu, Da Pang
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引用次数: 0

摘要

代谢重编程和表观遗传修饰是癌症的两个标志。蛋白质赖氨酸乳酸化(Kla)是一种新型的糖酵解乳酸引发的翻译后修饰。然而,Kla在乳腺癌(BC)中的作用在很大程度上仍然未知。western blot和免疫组化(IHC)对BC组织的染色显示,BC组织中Kla水平上调,Kla水平高与BC患者预后不良相关。一系列体外和体内实验表明,乳酸脱氢酶(LDH)抑制剂中断糖酵解或沉默LDHA和LDHB可抑制BC细胞的恶性行为。此外,对BC组织和细胞的4D无标记定量乳酸蛋白组学分析显示,乳酸化蛋白广泛存在于几个亚细胞区室中,并与各种癌症相关的生物学过程密切相关。值得注意的是,两个先前未被研究的组蛋白乳酸化位点,H4K79乳酸化(H4K79la)和H4K91乳酸化(H4K91la),在癌症组织和细胞中被鉴定为高乳酸化。通过染色质免疫沉淀测序(ChIP-seq)、RNA测序(RNA-seq)和TCGA-BRCA数据库的交叉分析,确定糖酵解基因乳酸脱氢酶A (LDHA)、磷酸甘油激酶1 (PGK1)和己糖激酶1 (HK1)是H4K79la和H4K91la表观遗传调控的潜在候选基因。糖酵解的药理抑制下调了H4K79和H4K91的乳酸化,抑制了糖酵解基因的表达,而乳酸钠则表现出相反的效果。e1a结合蛋白p300 (p300)在BC细胞中作为赖氨酸乳酸转移酶调节H4K79la和H4K91la,控制下游糖酵解基因的转录和表达。结果揭示了BC中糖酵解/H4K79la/H4K91la/糖酵解基因形成的一个有趣的正反馈回路,突出了代谢重编程与表观遗传调控之间的关系。这些发现为BC患者提供了新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer.

Metabolic reprogramming and epigenetic modification are two hallmarks of cancer. Protein lysine lactylation (Kla) is a novel type of glycolysis lactate-triggered posttranslational modification. However, the role of Kla in breast cancer (BC) remains largely unknown. Here, western blot, and immunohistochemical (IHC) staining of BC tissues revealed that global Kla levels were upregulated in BC tissues, and high levels of Kla were correlated with poor prognosis of patients with BC. A series of in vitro and in vivo assays demonstrated that interruption of glycolysis by lactate dehydrogenase (LDH) inhibitor or silencing LDHA and LDHB repressed the malignant behaviors of BC cells. Moreover, 4D label-free quantitative lactylproteomics analysis of BC tissues and cells revealed that lactylated proteins widely existed in several subcellular compartments and were closely associated with various cancer-related biological processes. Notably, two previously unresearched sites of histone lactylation, H4K79 lactylation (H4K79la) and H4K91 lactylation (H4K91la), were identified to be hyperlactylated in cancer tissues and cells. Glycolytic genes, such as lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and hexokinase 1 (HK1) were identified to be the potential candidate genes epigenetically regulated by H4K79la and H4K91la by intersecting through chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and TCGA-BRCA database. Pharmacological inhibition of glycolysis downregulated H4K79 and H4K91 lactylation and suppressed the expression of glycolytic genes, whereas treatment with sodium lactate exhibited the opposite effects. Additionally, E1A-binding protein p300 (P300) acted as lysine lactyltransferase to regulate H4K79la and H4K91la, and control the transcription and expression of downstream glycolytic genes in BC cells. The results revealed an intriguing positive feedback loop formed by glycolysis/H4K79la/H4K91la/glycolytic genes in BC, highlighting the relationship between metabolic reprogramming and epigenetic regulation. These findings provide new therapeutic targets for patients with BC.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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