YEATS2 promotes malignant phenotypes of esophageal squamous cell carcinoma via H3K27ac activated-IL6ST.

IF 4.6 2区生物学 Q2 CELL BIOLOGY Frontiers in Cell and Developmental Biology Pub Date : 2025-02-18 eCollection Date: 2025-01-01 DOI:10.3389/fcell.2025.1497290

Yuanfang Zhai, Fanyu Zhang, Xiaoyu Shi, Siwei Zou, Xiaoling Hu, Chengyuan Shan, Ling Zhang, Binbin Zou, Xin Yang, Pengzhou Kong, Xiaolong Cheng

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Abstract

Introduction: Histone acetylation modifications can regulate gene transcription and play crucial roles in multiple tumorigeneses processes. YEATS domain proteins are one important type of acetylation readers. We have found significant mutations and copy number amplifications of YEATS domain containing 2 (YEATS2) gene in esophageal squamous cell carcinoma (ESCC) through whole genome sequencing (WGS). However, the function and molecular mechanism of YEATS2 in ESCC remain elusive.

Methods: Chi-squared test and Kaplan-Meier methods were used to analyze the clinical significance of YEATS2. MTT, Colony Formation Assay, Transwell, Scratch Wound Healing, subcutaneous tumorigenesis model and lung metastatic tumor model were performed to detect YEATS2 effect on the proliferation and migration ability of ESCC cells in vivo and in vitro Co-IP-based mass spectrum (MS) assays and Chromatin immunoprecipitation (ChIP) were performed to explore the molecular mechanism of YEATS2 function in ESCC.

Results: ESCC patients with copy number amplification of YEATS2 had shorter postoperative survival. Furthermore, YEATS2 expression was positively correlated with copy number amplification. We have also found that YEATS2 expression was significantly upregulated in ESCC tissues and was correlated closely with the differentiation degree of ESCC cells. The results of in vivo and in vitro experiments revealed that YEATS2 enhanced the abilities of ESCC cells to proliferate and migrate. Mechanistically, YEATS2 activated NF-κB signaling to promote ESCC progression. YEATS2 and H3K27 acetylation (H3K27ac) were both enriched in the promoter region of IL6ST, which is involved in the regulation of YEATS2 on NF-κB signaling. Additionally, YEATS2 could recruit TAF15 and KAT5 to enhance H3K27ac enrichment in the promoter region of IL6ST to regulate its expression.

Conclusion: In conclusion, YEATS2 might function as a potential driver gene and a potential therapeutic target in ESCC.

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YEATS2通过H3K27ac激活的il6st促进食管鳞状细胞癌的恶性表型。

组蛋白乙酰化修饰可调控基因转录，在多种肿瘤发生过程中发挥重要作用。叶氏结构域蛋白是一种重要的乙酰化读卡器。通过全基因组测序（WGS），我们发现食管鳞状细胞癌（ESCC）中YEATS结构域2 （YEATS2）基因存在显著突变和拷贝数扩增。然而，YEATS2在ESCC中的功能和分子机制尚不清楚。方法：采用卡方检验和Kaplan-Meier法分析YEATS2的临床意义。采用MTT、菌落形成实验、Transwell、划伤愈合、皮下肿瘤发生模型和肺转移瘤模型检测YEATS2对ESCC细胞体内增殖和迁移能力的影响，采用co - ip质谱（MS）和染色质免疫沉淀（ChIP）技术探讨YEATS2在ESCC中作用的分子机制。结果：YEATS2拷贝数扩增的ESCC患者术后生存期较短。此外，YEATS2的表达与拷贝数扩增呈正相关。我们还发现YEATS2在ESCC组织中表达显著上调，且与ESCC细胞分化程度密切相关。体内和体外实验结果显示，YEATS2增强了ESCC细胞的增殖和迁移能力。在机制上，YEATS2激活NF-κB信号，促进ESCC进展。YEATS2和H3K27乙酰化（H3K27ac）均富集于IL6ST启动子区，参与YEATS2对NF-κB信号的调控。此外，YEATS2可以招募TAF15和KAT5，增强IL6ST启动子区域H3K27ac的富集，从而调控其表达。结论：YEATS2可能是ESCC的潜在驱动基因和潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Cell and Developmental Biology Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

9.70

自引率

3.60%

发文量

2531

审稿时长

12 weeks

期刊介绍： Frontiers in Cell and Developmental Biology is a broad-scope, interdisciplinary open-access journal, focusing on the fundamental processes of life, led by Prof Amanda Fisher and supported by a geographically diverse, high-quality editorial board. The journal welcomes submissions on a wide spectrum of cell and developmental biology, covering intracellular and extracellular dynamics, with sections focusing on signaling, adhesion, migration, cell death and survival and membrane trafficking. Additionally, the journal offers sections dedicated to the cutting edge of fundamental and translational research in molecular medicine and stem cell biology. With a collaborative, rigorous and transparent peer-review, the journal produces the highest scientific quality in both fundamental and applied research, and advanced article level metrics measure the real-time impact and influence of each publication.