KMT2D/ZNF460-induced COL9A1-mediated extracellular matrix stiffness maintains the cancer stem cell pool to promote colorectal cancer progression.

IF 5.3 2区医学 Q2 CELL BIOLOGY

Cell Biology and Toxicology Pub Date : 2025-07-01 DOI:10.1007/s10565-025-10053-3

Chengxin Song, Jingmin Xue, Wenjie Song, Xinyu Yue, Yixiu Xia, Peng Han

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Abstract

Collagen is a central component of the extracellular matrix (ECM) in tissues, and ECM can promote tumor cell immune evasion. Our research aimed to expound the biological function of the collagen alpha-1(IX) chain (COL9A1) in colorectal cancer (CRC) and the upstream mechanism regarding KMT2D/ZNF460. COL9A1 contributed to maintaining colorectal cancer stem cells (CCSC) self-renewal and proliferative capacity, and COL9A1 knockdown attenuated CCSC stemness, which was activated by 20.0 kPa polyacrylamide gels. Silencing of COL9A1 hampered tumor growth and stemness in mice induced by AOM/DSS and improved the tumor microenvironment (TME) in xenograft-bearing mice. Mechanistically, KMT2D promoted COL9A1 expression by mediating H3K4me1 modification of the enhancer and recruiting ZNF460. In the presence of attenuated KMT2D signaling, its effect on CCSC stemness and CRC progression was similar to that of knockdown of COL9A1, both of which have therapeutic benefits for CRC tumors. Again, the reactivation of COL9A1 reversed this trend. In conclusion, KMT2D mediates H3K4me1 modification of enhancers and recruits ZNF460 to activate COL9A1, which enhances ECM stiffness and self-renewal of CCSC to remodel TME, contributing to CRC progression.

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KMT2D/ znf460诱导的col9a1介导的细胞外基质刚度维持癌症干细胞库，促进结直肠癌进展。

胶原蛋白是组织中细胞外基质（extracellular matrix， ECM）的核心成分，ECM可以促进肿瘤细胞的免疫逃逸。我们的研究旨在阐明胶原α -1（IX）链（COL9A1）在结直肠癌（CRC）中的生物学功能及其与KMT2D/ZNF460相关的上游机制。COL9A1有助于维持结直肠癌干细胞（CCSC）的自我更新和增殖能力，COL9A1的敲低减弱了20.0 kPa聚丙烯酰胺凝胶激活的CCSC的干性。COL9A1的沉默抑制了AOM/DSS诱导小鼠肿瘤的生长和干性，改善了异种移植物小鼠的肿瘤微环境（TME）。机制上，KMT2D通过介导H3K4me1修饰增强子和募集ZNF460促进COL9A1表达。在KMT2D信号减弱的情况下，其对CCSC干性和CRC进展的影响与COL9A1的下调相似，两者对CRC肿瘤都有治疗益处。COL9A1的重新激活再次扭转了这一趋势。综上所述，KMT2D介导H3K4me1增强子修饰，并募集ZNF460激活COL9A1，从而增强ECM刚度和CCSC自我更新，重塑TME，促进CRC进展。

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

Cell Biology and Toxicology 生物-毒理学

CiteScore

9.90

自引率

4.90%

发文量

101

审稿时长

>12 weeks

期刊介绍： Cell Biology and Toxicology (CBT) is an international journal focused on clinical and translational research with an emphasis on molecular and cell biology, genetic and epigenetic heterogeneity, drug discovery and development, and molecular pharmacology and toxicology. CBT has a disease-specific scope prioritizing publications on gene and protein-based regulation, intracellular signaling pathway dysfunction, cell type-specific function, and systems in biomedicine in drug discovery and development. CBT publishes original articles with outstanding, innovative and significant findings, important reviews on recent research advances and issues of high current interest, opinion articles of leading edge science, and rapid communication or reports, on molecular mechanisms and therapies in diseases.