Xie Si-An, Li Xue, Yin Min-Yue, Du Feng, Zhang Shu-Tian, Zhu Sheng-Tao
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, State Key Laboratory of Digestive Health, Beijing, 100050, China.
Exp Hematol Oncol. 2025 Aug 27;14(1):111. doi: 10.1186/s40164-025-00704-w.
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（ECM）构成肿瘤微环境的主要支架，基质硬度作为一种关键的物理信号，调节癌症进展。然而，基质硬度对结直肠癌（CRC）进展的影响仍不清楚。本研究旨在阐明底物硬度在调节DNA N6-甲基腺嘌呤（6mA）修饰及其与CRC进展关联中的作用。我们观察到，与正常对照相比，CRC细胞和组织中的DNA 6mA水平显著降低，且随着CRC分期的推进而逐渐下降。CRC组织硬度与DNA 6mA水平之间存在负相关。6mA去甲基化酶ALKBH1被确定为CRC的不良预后指标，并对增加的底物硬度作出反应，与CRC增殖增强相关。机制上，ALKBH1响应底物硬化介导DNA 6mA去甲基化，从而调节基因转录并促进CRC肿瘤发生。值得注意的是，ALKBH1在P53基因敲除的CRC细胞中失去其增殖作用，而催化失活的ALKBH1突变体抑制肿瘤发生。此外，ALKBH1通过损害P53与CDKN1A启动子区域的结合来降低CDKN1A的表达。总体而言，我们的研究结果表明，ALKBH1作为连接基质硬度与DNA 6mA去甲基化的关键介质，严重驱动CRC进展并突出其治疗潜力。这些结果强调了DNA 6mA修饰在CRC发展和肿瘤对微环境信号反应中的重要性。
