NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation
Abstract DNA methylation regulators play critical roles in modulating oncogenic driver genes in cancers. However, the precise mechanisms through which these DNA methylation regulators influence oncogenesis and clinical therapy have yet to be fully elucidated. This study reveals that hypermethylation...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202413508 |
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| author | Xukun Li Dandan Fan Yong Li Jian Yuan Wanyuan Sun Qinghao Zhu Ling Qi Xueling Wu Jiahui Cai Tongyang Gong Ning Zhao Jianzhong Su Zhihua Liu Hongyan Chen |
| author_facet | Xukun Li Dandan Fan Yong Li Jian Yuan Wanyuan Sun Qinghao Zhu Ling Qi Xueling Wu Jiahui Cai Tongyang Gong Ning Zhao Jianzhong Su Zhihua Liu Hongyan Chen |
| author_sort | Xukun Li |
| collection | DOAJ |
| description | Abstract DNA methylation regulators play critical roles in modulating oncogenic driver genes in cancers. However, the precise mechanisms through which these DNA methylation regulators influence oncogenesis and clinical therapy have yet to be fully elucidated. This study reveals that hypermethylation of under‐methylated regions (UMRs) within gene bodies is involved in the activation of oncogenic homeobox genes, particularly NKX2‐5 and LHX1, in esophageal squamous cell carcinoma (ESCC). Mechanistically, NKX2‐5 and LHX1 synergistically bind to the promoter region of UHRF1, thereby augmenting its transcription. In turn, UHRF1 orchestrates the recruitment of DNMT1/DNMT3A, alongside NKX2‐5 and LHX1, to the UMRs of these genes, thereby increasing DNA methylation levels and their expression. This intricate interplay forms a positive transcriptional feedback loop between NKX2‐5/LHX1 and UHRF1, thus promoting the overexpression of all three genes and ultimately facilitating tumor growth. Notably, concurrent inhibition of UHRF1 and DNMTs impedes tumor growth by suppressing NKX2‐5 and LHX1 expression. Overall, this study identifies a positive feedback regulatory circuitry underlying the UMR hypermethylation‐mediated activation of oncogenic drivers in ESCC and proposes a promising therapeutic strategy for ESCC patients. |
| format | Article |
| id | doaj-art-2ab1c7fee11b4fd988d8354640c670d2 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2ab1c7fee11b4fd988d8354640c670d22025-08-20T02:02:16ZengWileyAdvanced Science2198-38442025-05-011220n/an/a10.1002/advs.202413508NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic DysregulationXukun Li0Dandan Fan1Yong Li2Jian Yuan3Wanyuan Sun4Qinghao Zhu5Ling Qi6Xueling Wu7Jiahui Cai8Tongyang Gong9Ning Zhao10Jianzhong Su11Zhihua Liu12Hongyan Chen13The State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang 325101 P. R. ChinaDepartment of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang 325101 P. R. ChinaThe State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang 325101 P. R. ChinaDepartment of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaThe State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaThe State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaThe State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaThe State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaOujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang 325101 P. R. ChinaThe State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaThe State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 P. R. ChinaAbstract DNA methylation regulators play critical roles in modulating oncogenic driver genes in cancers. However, the precise mechanisms through which these DNA methylation regulators influence oncogenesis and clinical therapy have yet to be fully elucidated. This study reveals that hypermethylation of under‐methylated regions (UMRs) within gene bodies is involved in the activation of oncogenic homeobox genes, particularly NKX2‐5 and LHX1, in esophageal squamous cell carcinoma (ESCC). Mechanistically, NKX2‐5 and LHX1 synergistically bind to the promoter region of UHRF1, thereby augmenting its transcription. In turn, UHRF1 orchestrates the recruitment of DNMT1/DNMT3A, alongside NKX2‐5 and LHX1, to the UMRs of these genes, thereby increasing DNA methylation levels and their expression. This intricate interplay forms a positive transcriptional feedback loop between NKX2‐5/LHX1 and UHRF1, thus promoting the overexpression of all three genes and ultimately facilitating tumor growth. Notably, concurrent inhibition of UHRF1 and DNMTs impedes tumor growth by suppressing NKX2‐5 and LHX1 expression. Overall, this study identifies a positive feedback regulatory circuitry underlying the UMR hypermethylation‐mediated activation of oncogenic drivers in ESCC and proposes a promising therapeutic strategy for ESCC patients.https://doi.org/10.1002/advs.202413508DNA methylationLHX1NKX2‐5transcriptional dysregulationUHRF1 |
| spellingShingle | Xukun Li Dandan Fan Yong Li Jian Yuan Wanyuan Sun Qinghao Zhu Ling Qi Xueling Wu Jiahui Cai Tongyang Gong Ning Zhao Jianzhong Su Zhihua Liu Hongyan Chen NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation Advanced Science DNA methylation LHX1 NKX2‐5 transcriptional dysregulation UHRF1 |
| title | NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation |
| title_full | NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation |
| title_fullStr | NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation |
| title_full_unstemmed | NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation |
| title_short | NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation |
| title_sort | nkx2 5 lhx1 and uhrf1 establishing a positive feedback regulatory circuitry drives esophageal squamous cell carcinoma through epigenetic dysregulation |
| topic | DNA methylation LHX1 NKX2‐5 transcriptional dysregulation UHRF1 |
| url | https://doi.org/10.1002/advs.202413508 |
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