TCF4 and CtBP1 Repress LEF1 to Maintain a TCF4-centric Transcriptional Program in Colon Cancer.

Brown, M. A.; Yaghoubi, S.; Kamlah, J.; Chen, W.-D.; Zong, D.; Khorasani, S. T.; Zhan, T.; Boutros, M.; Polo, J. C.; Meltzer, P. S.

doi:10.64898/2026.09.25.751839

bioRxiv · 10.64898/2026.09.25.751839

TCF4 and CtBP1 Repress LEF1 to Maintain a TCF4-centric Transcriptional Program in Colon Cancer.

Brown, M. A.·Yaghoubi, S.·Kamlah, J.·Chen, W.-D.·Zong, D.·Khorasani, S. T.·Zhan, T.·Boutros, M.·Polo, J. C.·Meltzer, P. S.

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Abstract

Abstract The canonical WNT signaling pathway guides cell growth throughout the human lifespan. In adults, WNT plays an essential role in tissue homeostasis by maintaining tissue stem cells. In the intestine, the WNT transcription factor, TCF4, is necessary for stem cell maintenance. Aberrant activation of WNT signaling is generally accepted as an initiating event in colon cancer, leading to constitutive TCF4 activity. To investigate the role of this key transcription factor in global gene regulation, we abrogated TCF4 expression in colon cancer cells. Loss of TCF4 function resulted in the over-expression of the WNT transcription factor, LEF1. LEF1 was transcriptionally competent and over-compensated for TCF4 (TCF7L2) silencing in a WNT reporter assay. TCF4 enlisted the transcriptional repressor CtBP1, and bound the LEF1 promoter, indicative of direct repression. TCF4 and LEF1 drove different transcriptional programs, with TCF4 favoring MYC and cell cycle progression, while LEF1 favored immune-related gene signatures. TCF4 was the primary regulator of MYC expression, yet also the mediator of LEF1 repression, suggestive of competition centered on TCF4 transcriptional output despite the {beta}-catenin saturated colon cancer nucleus. We conclude that TCF4 has dual activator-repressor activity in colon cancer.

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Brown, M. A., Yaghoubi, S., Kamlah, J., Chen, W.-D., Zong, D., Khorasani, S. T., Zhan, T., Boutros, M., Polo, J. C., Meltzer, P. S.. 2026-09-28. TCF4 and CtBP1 Repress LEF1 to Maintain a TCF4-centric Transcriptional Program in Colon Cancer.. https://doi.org/10.64898/2026.09.25.751839

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