Abstract
Colorectal Cancer (CRC) progression is a complex and dynamic process closely linked to TET2-mediated DNA demethylation. Distinct from our previous study on TET2 nuclear loss, which can be observed in the whole tumor progression process, the nuclear increase of TET2 was only observed in tumors at the beginning of metastasis. In addition, cells with nuclear TET2 were located at the bottom of the mucosa, which is the invasion front of CRC. All of these results suggested crucial roles of TET2 nuclear increase during tumor progression. Mechanistically, epithelial-mesenchymal transition (EMT) and the activation of the WNT pathway, which is normally recognized as tumor promotion events, were shown to correlate with the cytoplasm-nucleus shuttling of TET2, which is associated with tumor suppression. Nuclear TET2, in turn, mitigated further EMT and WNT activation, suggesting a negative feedback loop between TET2 and the EMT/WNT pathway. Such a negative feedback loop was further supported by single-cell RNA sequencing (scRNA-seq) analysis of both the CRC progression models and the clinical CRC samples. Together, these findings indicate that the tumor inhibition role of EMT/WNT pathway and TET2 is an intrinsic brake on cancer progression, which represents a potential therapeutic target for CRC.
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Data availability
The RNA-seq and scRNA-seq results generated in this study are available at Gene Expression Ominibus (GEO) under accession number GSE269621 [Secure token: qpsdyesijtwzpul] & GSE188329 [Secure token: ivknawwarxahbct]. The other published dataset (GSE97693, TCGA cancer datasets in UCSC Xena datasets) [22] used in the current studies were listed in Supplementary Table S2. This study did not generate code. Data are available on reasonable request.
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Acknowledgements
This work was supported by the Guangdong Basic and Applied Basic Research Foundation (2024B1515040020), the National Key R&D Program of China (2024YFA1108201 and 2024YFA1802300), the National Natural Science Foundation of China (U21A20203 and 32170741), the Science and Technology Program of Guangzhou (202201011654), the Science and Technology Planning Project of Guangdong Province (2023B1212060050 and 2023B1212120009), Guangdong Special Support Program (2023TX07A051), Postdoctoral Research Project Funding (B202500701), the Tertiary Education Scientific research project of Guangzhou Municipal Education Bureau (2024312185), The Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022362), Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (GIBHBRP23-01, GIBHBRP24-01, and GIBHBRP24-02), the Human Cell Lineage Atlas Facility (DSS010403-01) and the Research Funds from Health@InnoHK Program launched by Innovation Technology Commission of the Hong Kong SAR, P. R. China.
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HZ supervised the work and wrote the manuscript. ZH, XL, and JH supervised and performed the work related to paraffin section and tissue array samples. HZ and CL designed the experiments and analyzed the data. CL, FM, JH, and LD contributed equally to the manuscript by performing most experiments. YH, QG, KZ, YW, HG, SC, TY, YZ, YLW, LL, QR, MH, HS, LLL, and LG helped perform or repeat different types of experiments.
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All animal studies were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80-23) and were approved by the Institutional Review Board in Guangzhou Institutes of Biomedicine and Health (No.2019061).
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Li, C., Meng, F., He, J. et al. Cytoplasm-nucleus shuttling of TET2: an intrinsic brake in colorectal cancer progression. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08418-5
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DOI: https://doi.org/10.1038/s41419-026-08418-5
