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SOX2 reprograms the methionine cycle by RMST-conferred AHCY sequestration in cancer

This article is a preprint and has not been certified by peer review.

Authors

    Iqra Ishrat,  
    Iqra Ishrat
    • School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China
    Zafar Iqbal Bhat,  
    Zafar Iqbal Bhat
    • Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518132, China
    Zhihua Guo,   Hilary K. Ho,  
    Hilary K. Ho
    • School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China
    Ruiqi Ma,   Qing Tang,  
    Qing Tang
    • Division of Life Sciences and the Biotechnology Research Institute, Hong Kong University of Science and Technology; Hong Kong, 999077, China
    Jinghao Liang,   Yanxi Huang,  
    Yanxi Huang
    • Division of Life Sciences and the Biotechnology Research Institute, Hong Kong University of Science and Technology; Hong Kong, 999077, China
    • State Key Laboratory of Molecular Neuroscience and the Molecular Neuroscience Center, Hong Kong University of Science and Technology; Hong Kong, 999077, China
    Lei Zhang,  
    Lei Zhang
    • School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China
    Yung Hou Wong,  
    Yung Hou Wong
    • Division of Life Sciences and the Biotechnology Research Institute, Hong Kong University of Science and Technology; Hong Kong, 999077, China
    Nada Jabado,   Weiqiang Yin,   Hong Kee Tan,   Justin L. Tan
    Justin L. Tan
Categories
Cell Biology

Abstract

Transcription factors drive gene expression dysregulation in cancer. However, non-canonical oncogenic mechanisms of these factors are unclear. Utilizing function-centric proteomics to discover RNA-dependent protein-protein interactions, we uncovered an unexpected interaction between transcription factor oncogene SOX2 and methionine cycle enzyme AHCY. Immunofluorescence and CUT&RUN revealed that SOX2 expression sequesters AHCY to the chromatin. A candidate RNA-immunoprecipitation screen identified non-coding RNA RMST as a mediator of the SOX2 and AHCY interaction. The SOX2-AHCY interaction is reduced upon RMST knockdown. SOX2 expression sequesters RMST and AHCY in the nucleus, an activity dependent on the RNA-binding Arginine Rich Motif (ARM) domain of SOX2. Metabolite profiling revealed that SOX2 expression alters methionine cycle intermediates, particularly at the AHCY catalyzed step. Methylation precursor S-adenosylmethionine (SAM) production is also inhibited by SOX2. These metabolic changes are rescued with SOX2 ARM mutation. Whole genome bisulfite sequencing revealed that SOX2 expression induces DNA hypomethylation in cancer cells. DNA hypomethylation and its downstream DNA damage effect are rescued with SAM supplementation or SOX2 ARM mutation. These data suggest that SOX2 mis-expression in cancer sequesters AHCY, through an RMST adaptor, in the nucleus. This reduces the availability of cytoplasmic AHCY to participate in the methionine cycle, reprograming this metabolic process. As a result, SAM levels are reduced, causing DNA hypomethylation and downstream DNA damage. Our findings were validated in cancer patient biopsies. Strikingly, knockdown and pharmacological inhibition of AHCY targets SOX2-expressing cancer cells in culture and in vivo. This suggests that low SAM levels, induced by decreased cytoplasmic AHCY, sensitize SOX2-expressing cancer cells to AHCY inhibition. Overall, our results suggest that a transcription factor can coopt a non-coding RNA to perform non-canonical metabolic reprograming, creating a druggable metabolic dependency in transcription factor-driven cancer.

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.01.04.000079

Submission ID:

79

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Posted

2026-01-05

How to Cite

Ishrat, I., Bhat, Z. I., Guo, Z., Ho, H. K., Ma, R., Tang, Q., Liang, J., Huang, Y., Zhang, L., Wong, Y. H., Jabado, N., Yin, W., Tan, H. K., & Tan, J. L. (2026). SOX2 reprograms the methionine cycle by RMST-conferred AHCY sequestration in cancer. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.01.04.000079

Declaration of Competing Interests

The authors declare no competing interests to disclose.

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