Extracellular matrix stiffness reduces DNA 6 ma level to facilitate colorectal cancer progression via disrupting P53 binding to CDKN1A promoter.

IF 13.5 1区 医学 Q1 HEMATOLOGY
Si-An Xie, Xue Li, Min-Yue Yin, Feng Du, Shu-Tian Zhang, Sheng-Tao Zhu
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Abstract

The extracellular matrix (ECM) forms the primary scaffold of the tumor microenvironment, with matrix stiffness serving as a critical physical cue that modulates cancer progression. However, the impact of matrix stiffness on colorectal cancer (CRC) progression remains elusive. This study aimed to elucidate the role of substrate stiffness in regulating DNA N6-methyladenine (6 mA) modifications and their association with CRC progression. We observed significantly reduced DNA 6 mA levels in CRC cells and tissues compared to normal controls, which progressively declined with advancing CRC stages. A negative correlation was identified between CRC tissue stiffness and DNA 6 mA levels. The 6 mA demethylase ALKBH1 was identified as a poor prognostic indicator in CRC and responded to increased substrate stiffness, correlating with enhanced CRC proliferation. Mechanistically, ALKBH1 mediated DNA 6 mA demethylation in response to substrate stiffening, thereby modulating gene transcription and promoting CRC tumorigenesis. Notably, ALKBH1 lost its proliferative effect in P53-knockout CRC cells, while a catalytically inactive ALKBH1 mutant suppressed oncogenesis. Furthermore, ALKBH1 diminished CDKN1A expression by impairing P53 binding to the CDKN1A promoter region. Collectively, our findings demonstrate that ALKBH1 acts as a pivotal mediator linking matrix stiffness to DNA 6 mA demethylation, critically driving CRC progression and highlighting its therapeutic potential. These results underscore the importance of DNA 6 mA modifications in CRC development and tumor response to microenvironmental cues.

细胞外基质硬度降低DNA 6ma水平,通过破坏P53与CDKN1A启动子的结合促进结直肠癌的进展。
细胞外基质(ECM)形成肿瘤微环境的主要支架,基质刚度作为调节癌症进展的关键物理线索。然而,基质硬度对结直肠癌(CRC)进展的影响仍然难以捉摸。本研究旨在阐明底物硬度在调节DNA n6 -甲基腺嘌呤(6ma)修饰中的作用及其与结直肠癌进展的关系。我们观察到,与正常对照相比,结直肠癌细胞和组织中的DNA 6 mA水平显著降低,随着结直肠癌分期的进展,DNA 6 mA水平逐渐下降。结直肠癌组织硬度与DNA 6ma水平呈负相关。6 mA去甲基化酶ALKBH1被认为是CRC的一个不良预后指标,对底物硬度增加有反应,与CRC增殖增强相关。在机制上,ALKBH1介导DNA 6ma去甲基化以响应底物硬化,从而调节基因转录并促进结直肠癌的发生。值得注意的是,ALKBH1在p53敲除的CRC细胞中失去了增殖作用,而催化失活的ALKBH1突变体抑制了肿瘤的发生。此外,ALKBH1通过损害P53与CDKN1A启动子区域的结合来减少CDKN1A的表达。总的来说,我们的研究结果表明,ALKBH1是将基质硬度与DNA 6ma去甲基化联系起来的关键介质,关键地推动了结直肠癌的进展,并突出了其治疗潜力。这些结果强调了DNA 6ma修饰在结直肠癌发展和肿瘤对微环境信号反应中的重要性。
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
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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