UBR7和PRMT5之间的相互作用通过调节糖酵解和免疫微环境促使PDAC对吉西他滨产生耐药性。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Maoxiao Feng, Qinlian Jiao, Yidan Ren, Xiaoyan Liu, Zihan Gao, Zhengjun Li, Yunshan Wang, Miaoqing Zhao, Lei Bi
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引用次数: 0

摘要

胰腺导管腺癌(PDAC)是一种常见的消化道恶性肿瘤。虽然吉西他滨和其他治疗药物对晚期和转移性胰腺癌患者有效,但耐药性严重限制了它们的使用。然而,人们对吉西他滨在胰腺癌中的耐药机制知之甚少。在本研究中,我们进行了ATAC-seq、ChIP-seq和RNA-seq测序,以比较吉西他滨耐药或不耐药的胰腺癌患者来源肿瘤异种移植(PDX)模型的染色质可及性和基因表达。通过分析这些测序数据,我们发现吉西他滨耐药组织的PDX模型中染色质可及性发生了巨大变化,并确定了一个关键基因UBR7,它在介导吉西他滨耐药方面发挥着重要作用。进一步的研究发现,删除 UBR7 会显著增加胰腺癌的发生和免疫抑制微环境。从机理上讲,UBR7 的耗竭增加了 PRMT5 的稳定性,从而促进了胰腺癌细胞中的糖酵解。最后,阻断 PRMT5 的抑制剂(DS-437)显著降低了 UBR7 贫化导致的胰腺癌对吉西他滨的耐药性。总之,我们的研究结果表明,UBR7-PRMT5 轴是 PDAC 的一个关键代谢调节因子,也是临床治疗 PDAC 吉西他滨耐药的一个有希望的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The interaction between UBR7 and PRMT5 drives PDAC resistance to gemcitabine by regulating glycolysis and immune microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a common malignant tumor of the digestive tract. Although gemcitabine and other therapeutic agents are effective in patients with advanced and metastatic pancreatic cancer, drug resistance has severely limited their use. However, the mechanisms of gemcitabine resistance in pancreatic cancer are poorly understood. In this study, ATAC-seq, ChIP-seq, and RNA-seq were performed to compare chromatin accessibility and gene expression in a patient-derived tumor xenograft (PDX) model of pancreatic cancer with or without gemcitabine resistance. Analyzing these sequencing data, we found a dramatic change in chromatin accessibility in the PDX model of gemcitabine-resistant tissues and identified a key gene, UBR7, which plays an important role in mediating gemcitabine resistance. Further research found that depletion of UBR7 significantly increased pancreatic carcinogenesis and the immunosuppressive microenvironment. Mechanistically, depleted UBR7 increased the stability of PRMT5, thereby promoting glycolysis in pancreatic cancer cells. Finally, an inhibitor that blocks PRMT5 (DS-437) significantly reduced gemcitabine resistance in pancreatic cancer caused by UBR7 depletion. In conclusion, our results illustrate that the UBR7-PRMT5 axis is a key metabolic regulator of PDAC and a promising target for the clinical treatment of gemcitabine resistance in PDAC.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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