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Lyn/RUVBL1复合物通过染色质重塑调节花生四烯酸代谢促进结直肠癌肝转移。

The Lyn/RUVBL1 Complex Promotes Colorectal Cancer Liver Metastasis by Regulating Arachidonic Acid Metabolism Through Chromatin Remodeling.

作者信息

Zhang Zhenyu, Gao Yina, Qian Yuanyuan, Wei Bowen, Jiang Kexin, Sun Zhiwei, Zhang Feifan, Yang Mingming, Baldi Salem, Yu Xiaoqi, Zuo Yunfei, Ren Shuangyi

机构信息

Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China.

Department of Clinical Biochemistry, College of Laoratory Medicine, Dalian Medical University, Dalian, 116044, China.

出版信息

Adv Sci (Weinh). 2025 Feb;12(5):e2406562. doi: 10.1002/advs.202406562. Epub 2024 Dec 12.

DOI:10.1002/advs.202406562
PMID:39665272
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11792055/
Abstract

Liver metastasis is a common cause of death in colorectal cancer (CRC) patients, but epigenetic remodeling and metabolic reprogramming for CRC liver metastasis remain unclear. The study revealed that the Lyn/RUVBL1 complex is highly expressed in CRC and is closely correlated with liver metastasis. On the one hand, ATAC-seq and HiCut suggested that Lyn/RUVBL1 regulates the expression of TRIB3 through the POL II-mediated chromatin conformation of TRIB3 and thus the expression of β-catenin. This promotes the proliferation and migration of CRC through β-catenin-mediated upregulation of MMP9 and VEGF. On the other hand, metabolomics revealed that Lyn/RUVBL1 regulates the expression of PGE2 through the enzyme COX2, thereby promoting arachidonic acid (AA) metabolism. CUT-Tag showed that Lyn/RUVBL1 silencing reduces the H3K27ac level in the COX2 promoter. Then, it is found that COX2 is regulated by the transcription factor FOXA1. Lyn/RUVBL1 modulates AA metabolism by regulating the chromatin accessibility of FOXA1. AA metabolism promotes the metastasis of CRC by affecting β-catenin nuclear translocation and upregulating MMP9 and VEGF. These findings suggest that the Lyn/RUVBL1 complex mediates epigenetic remodeling to regulate the metabolic reprogramming of AA, highlighting its role in promoting the metastasis of CRC.

摘要

肝转移是结直肠癌（CRC）患者常见的死亡原因，但CRC肝转移的表观遗传重塑和代谢重编程仍不清楚。该研究表明，Lyn/RUVBL1复合物在CRC中高表达，且与肝转移密切相关。一方面，ATAC-seq和HiCut表明，Lyn/RUVBL1通过POL II介导的TRIB3染色质构象调节TRIB3的表达，进而调节β-连环蛋白的表达。这通过β-连环蛋白介导的MMP9和VEGF上调促进CRC的增殖和迁移。另一方面，代谢组学显示，Lyn/RUVBL1通过COX2酶调节PGE2的表达，从而促进花生四烯酸（AA）代谢。CUT-Tag表明，Lyn/RUVBL1沉默会降低COX2启动子中的H3K27ac水平。然后，发现COX2受转录因子FOXA1调节。Lyn/RUVBL1通过调节FOXA1的染色质可及性来调节AA代谢。AA代谢通过影响β-连环蛋白核转位和上调MMP9和VEGF促进CRC转移。这些发现表明，Lyn/RUVBL1复合物介导表观遗传重塑以调节AA的代谢重编程，突出了其在促进CRC转移中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c32/11792055/5845ea133e7b/ADVS-12-2406562-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c32/11792055/5845ea133e7b/ADVS-12-2406562-g003.jpg

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