One-carbon metabolism controls colorectal cancer cell state and chemosensitivity through chromatin remodeling
- 1Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
Abstract
Folate is co-administered with fluoropyrimidines in colorectal cancer to potentiate thymidylate synthase inhibition, yet its therapeutic effects are paradoxically inconsistent across disease and treatment settings. Here we show that one-carbon metabolism remodels epithelial identity before treatment and thereby alters fluoropyrimidine response. Folate restoration shifted colorectal cancer cells along a polarized epithelial axis from a stem-like toward a differentiated state, whereas folate deprivation favored the opposite configuration. These pretreatment states differed markedly in 5-fluorouracil sensitivity. Folate restoration increased sensitivity across colorectal cancer cell lines and patient-derived organoids, whereas folate deprivation or methotrexate increased therapy-induced senescence. State-dependent sensitivity was not explained by proliferation alone, as stem-like cells were least responsive under the same conditions in which their S-phase occupancy was highest. Mechanistically, folate restoration increased methylation potential, supported EZH2-dependent H3K27me3 remodeling, reorganized chromatin accessibility and transcription-factor engagement, and reduced canonical WNT activity. In human colorectal tissue, stem-like program activity was higher and differentiation program activity lower in carcinoma than in normal mucosa, with adenomas intermediate, a pattern opposite to folate-induced remodeling. Folate is therefore not merely a cofactor for thymidylate synthase inhibition but an instructive metabolic regulator of the epithelial state that stratifies fluoropyrimidine response.
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BibTeX
@misc{vizkeleti2026onecarbon,
title = {{One-carbon metabolism controls colorectal cancer cell state and chemosensitivity through chromatin remodeling}},
author = {L. Vizkeleti and C. Kiss and V. Tisza and A. Zichy and A. Markovics and A. Kalmar and P. Szabo and I. Csabai and L. Pongor and S. Spisak and B. Molnar},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755690},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755690v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - One-carbon metabolism controls colorectal cancer cell state and chemosensitivity through chromatin remodeling
AU - L. Vizkeleti
AU - C. Kiss
AU - V. Tisza
AU - A. Zichy
AU - A. Markovics
AU - A. Kalmar
AU - P. Szabo
AU - I. Csabai
AU - L. Pongor
AU - S. Spisak
AU - B. Molnar
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755690
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755690v1
AB - Folate is co-administered with fluoropyrimidines in colorectal cancer to potentiate thymidylate synthase inhibition, yet its therapeutic effects are paradoxically inconsistent across disease and treatment settings. Here we show that one-carbon metabolism remodels epithelial identity before treatment and thereby alters fluoropyrimidine response. Folate restoration shifted colorectal cancer cells along a polarized epithelial axis from a stem-like toward a differentiated state, whereas folate deprivation favored the opposite configuration. These pretreatment states differed markedly in 5-fluorouracil sensitivity. Folate restoration increased sensitivity across colorectal cancer cell lines and patient-derived organoids, whereas folate deprivation or methotrexate increased therapy-induced senescence. State-dependent sensitivity was not explained by proliferation alone, as stem-like cells were least responsive under the same conditions in which their S-phase occupancy was highest. Mechanistically, folate restoration increased methylation potential, supported EZH2-dependent H3K27me3 remodeling, reorganized chromatin accessibility and transcription-factor engagement, and reduced canonical WNT activity. In human colorectal tissue, stem-like program activity was higher and differentiation program activity lower in carcinoma than in normal mucosa, with adenomas intermediate, a pattern opposite to folate-induced remodeling. Folate is therefore not merely a cofactor for thymidylate synthase inhibition but an instructive metabolic regulator of the epithelial state that stratifies fluoropyrimidine response.
ER -