Profiling of RUVBL2-Induced Transcriptome Alterations Highlights a Critical Role for Chromatin Remodeling in Ovarian Cancer

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
BioFactors Pub Date : 2025-08-04 DOI:10.1002/biof.70041
Renhao Xue, Yingjie Wang, Xiaomei Luo, Hao Zhang, Dongcheng Guan, Shuo Shi, Yu Wang
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引用次数: 0

Abstract

Cancerous transcriptome alterations in carcinoma cells could be originated from either genetic copy number changes or epigenetic reprogramming. Ovarian cancer (OV) is the most malignant gynecologic tumor, known for high aneuploidy with robust copy number alterations. However, low aneuploidy ovarian tumors are also frequently found, indicating an essential contribution of epigenetic factors during tumorigenesis and cancer development. Chromatin remodeling modulates the transcriptome epigenetically in a variety of cancer types, but its role in OV is still unclear. Hence, we investigated a cohort of 102 OV patients, analyzed transcriptomic and clinical data from public databases, and performed cellular experiments. We found that RUVBL2, a subunit of the INO80 complex, functions as the key oncogenic chromatin remodeler in OV. RUVBL2 is upregulated in tumors, particularly in low-aneuploidy cases, and is associated with poor prognosis. RUVBL2 drives nucleosome dynamics and elevates chromatin accessibility selectively at promoter regions. The landscape of RUVBL2-dependent modulation of chromatin accessibility and the transcriptome exhibits activation of various transcription factors, especially the AP-1 family, and upregulation of a series of key genes, including CDKN3, MYBL2, and ZNF144, resulting in mediation of cell cycle and Hippo signaling pathway to promote DNA synthesis and cell proliferation. Hence, RUVBL2-dependent chromatin remodeling plays a key role in oncogenic reprogramming of the transcriptome in OV. These findings provide novel insights into the molecular etiology of OV and disclose potential biomarkers and drug targets.

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ruvbl2诱导的转录组改变在卵巢癌中染色质重塑中的关键作用
癌细胞的转录组改变可能源于遗传拷贝数的改变或表观遗传重编程。卵巢癌(OV)是最恶性的妇科肿瘤,以高非整倍性和强大的拷贝数改变而闻名。然而,低非整倍性卵巢肿瘤也经常被发现,这表明表观遗传因素在肿瘤发生和癌症发展过程中发挥了重要作用。染色质重塑在多种癌症类型中调控表观遗传转录组,但其在OV中的作用尚不清楚。因此,我们调查了102例OV患者,分析了公共数据库中的转录组学和临床数据,并进行了细胞实验。我们发现,INO80复合体的一个亚基RUVBL2在OV中起着关键的致癌染色质重塑剂的作用。RUVBL2在肿瘤中表达上调,特别是在低非整倍体病例中,并与预后不良相关。RUVBL2驱动核小体动力学并选择性地提高启动子区域的染色质可及性。ruvbl2依赖性染色质可及性和转录组的调控表现为激活多种转录因子,特别是AP-1家族,上调一系列关键基因,包括CDKN3、MYBL2和ZNF144,从而介导细胞周期和Hippo信号通路,促进DNA合成和细胞增殖。因此,ruvbl2依赖性染色质重塑在OV中转录组的致癌重编程中起关键作用。这些发现为OV的分子病因学提供了新的见解,并揭示了潜在的生物标志物和药物靶点。
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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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