Dysregulation of R-loop homeostasis shapes the immunosuppressive microenvironment and induces malignant progression in melanoma.

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yan Ouyang, Yan Gu, Shuqin Li, Xianpeng Wei, Yang Liu, Zejun Wang, Fuzhou Tang, Shichao Zhang
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引用次数: 0

Abstract

Dysregulated R-loop homeostasis leads to DNA replication stress and genomic instability, a major driver of cancer. However, the role of R-loops in melanoma development remains unclear. We established an R-loop scoring model based on a single-cell RNA sequencing dataset and evaluated the association between the R-loop score with the melanoma immune microenvironment and treatment response. We explored the role of CENPA-mediated changes in R-loop distribution during melanoma progression by DNA/RNA immunoprecipitation and sequencing and a series of functional experiments. We found that malignant cells with high R-loop scores may be involved in melanoma progression by modulating immune evasion, metabolic reprogramming, and cancer-related pathways. A cell communication analysis revealed that high-score R-loops play an important role in altering cell-cell interactions and limiting the CD8 + cytotoxic T cell response and T cell accumulation. CENPA silencing induced changes in R-loop distribution, upregulated Hippo signaling activity, and inhibited tumor cell proliferation and migration. Moreover, the R-loop score can predict the prognosis and immunotherapy effect of melanoma patients. Our work reveals the potential molecular mechanism by which abnormal R-loops promote melanoma progression, which may help develop anticancer therapies based on R-loops or R-loop regulators.

R环平衡失调会形成免疫抑制微环境,并诱导黑色素瘤的恶性发展。
R 环平衡失调会导致 DNA 复制压力和基因组不稳定性,这是癌症的一个主要驱动因素。然而,R环在黑色素瘤发展中的作用仍不清楚。我们基于单细胞RNA测序数据集建立了一个R环评分模型,并评估了R环评分与黑色素瘤免疫微环境和治疗反应之间的关联。我们通过DNA/RNA免疫沉淀和测序以及一系列功能实验,探索了黑色素瘤进展过程中CENPA介导的R环分布变化的作用。我们发现,R环得分高的恶性细胞可能通过调节免疫逃避、代谢重编程和癌症相关通路参与了黑色素瘤的进展。细胞通讯分析表明,高分R环在改变细胞-细胞相互作用、限制CD8 +细胞毒性T细胞反应和T细胞积累方面发挥着重要作用。CENPA沉默会诱导R环分布的变化,上调Hippo信号活性,抑制肿瘤细胞的增殖和迁移。此外,R-loop评分还能预测黑色素瘤患者的预后和免疫治疗效果。我们的研究揭示了异常R环促进黑色素瘤进展的潜在分子机制,这可能有助于开发基于R环或R环调节剂的抗癌疗法。
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
Apoptosis
Apoptosis 生物-生化与分子生物学
CiteScore
9.10
自引率
4.20%
发文量
85
审稿时长
1 months
期刊介绍: Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.
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