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Updated: Sep 29, 2025
07:33
In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
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DOT1L affects colorectal carcinogenesis via altering T cell subsets and oncogenic pathway
Danfeng Sun1, Weichao Wang1, Fangfang Guo1
1Departments of Surgery,University of Michigan, Ann Arbor, Michigan, United States.
Oncoimmunology
|March 21, 2022
Summary
DOT1L in intestinal epithelial cells regulates inflammation and Wnt/β-catenin signaling, inhibiting colorectal cancer development. Targeting DOT1L may offer a new strategy for colorectal cancer prevention.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Chronic inflammation and oncogenic pathway activation are critical in colorectal cancer (CRC) pathogenesis.
- Intrinsic mechanisms linking inflammation and cancer signaling in CRC remain poorly understood.
Purpose of the Study:
- To investigate the role of DOT1L (histone methyltransferase) in intestinal epithelial cells (IECs) in CRC development.
- To elucidate the molecular mechanisms by which DOT1L influences inflammation and oncogenic signaling in CRC.
Main Methods:
- IEC-specific deletion of Dot1l in Apc- and AOM-DSS-induced CRC mouse models.
- Analysis of H3K79 dimethylation (H3K79me2) levels, immune cell populations (Treg, Th17, Th22), and Wnt/β-catenin signaling.
- Clinical correlation of H3K79me2 levels with tumor stage and Treg cells in human CRC patients.
Main Results:
- IEC-specific Dot1l deletion reduced H3K79me2, inhibited tumor formation, and alleviated inflammation in CRC models.
- Dot1l deficiency promoted regulatory T (Treg) cells while decreasing Th17 and Th22 cells, reducing microenvironment inflammation.
- Dot1l abrogation diminished Wnt/β-catenin signaling by reducing H3K79me2 at target gene promoters.
- Elevated tumor H3K79me2 levels in CRC patients correlated with advanced stages and inversely with Treg cells.
Conclusions:
- DOT1L acts as an intrinsic molecular link between chronic inflammation and oncogenic signaling in colorectal cancer.
- Targeting DOT1L may represent a novel therapeutic strategy to control colorectal carcinogenesis by modulating immune responses and oncogenic pathways.
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