{"title":"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。","authors":"Si-An Xie, Xue Li, Min-Yue Yin, Feng Du, Shu-Tian Zhang, Sheng-Tao Zhu","doi":"10.1186/s40164-025-00704-w","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"111"},"PeriodicalIF":13.5000,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382035/pdf/","citationCount":"0","resultStr":"{\"title\":\"Extracellular matrix stiffness reduces DNA 6 ma level to facilitate colorectal cancer progression via disrupting P53 binding to CDKN1A promoter.\",\"authors\":\"Si-An Xie, Xue Li, Min-Yue Yin, Feng Du, Shu-Tian Zhang, Sheng-Tao Zhu\",\"doi\":\"10.1186/s40164-025-00704-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":12180,\"journal\":{\"name\":\"Experimental Hematology & Oncology\",\"volume\":\"14 1\",\"pages\":\"111\"},\"PeriodicalIF\":13.5000,\"publicationDate\":\"2025-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382035/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Hematology & Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s40164-025-00704-w\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00704-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Extracellular matrix stiffness reduces DNA 6 ma level to facilitate colorectal cancer progression via disrupting P53 binding to CDKN1A promoter.
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.
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.