An Upstream <scp> <i>RUNX3</i> </scp> Enhancer, <scp>eR3</scp> (−18m/−28h), Regulates the Development of Gut‐Associated Anti‐Tumorigenic <scp>CD8</scp> <sup>+</sup> <scp>CD103</scp> <sup>+</sup> Cytotoxic T Lymphocytes in Mouse and Human
The RUNX3 gene is frequently involved in a variety of cancers and immunological diseases. Despite such widespread association with human diseases, the transcriptional regulation of RUNX3 remains elusive. Here we report the identification of an enhancer for Runx3, eR3(-18m/-28h), by employing a combination of in silico prediction and in vivo verification using zebrafish and mouse models. eR3 is active in CD8<sup>+</sup>CD103 (integrin α<sub>E</sub>)<sup>+</sup> cytotoxic T lymphocytes (CTLs) that reside in the intestinal epithelium via their interaction with the CD103 ligand, E-cadherin, on epithelial cells. Removal of eR3(-18m) specifically in CD8 T cells compromised the suppression of tumorigenesis in murine cancer models. In humans, single nucleotide polymorphisms (SNPs) in eR3(-28h) were overrepresented and were associated with weakened CTL activity in colorectal cancer patients. Together, our results indicate that eR3 plays a role in immune surveillance against gut-associated tumors by upregulating RUNX3 expression in specific CTLs.
Authors
- Junichi Matsuo (ORCID: https://orcid.org/0000-0002-2378-2370)
- Kazuyoshi Kohu
- Yoshiaki Ito (ORCID: https://orcid.org/0000-0002-9037-1184)
- Michelle Meng Huang Mok (ORCID: https://orcid.org/0000-0001-7030-266X)
- Phuong Cao Thi Ngoc (ORCID: https://orcid.org/0000-0002-3059-9179)
- Hilde Cheroutre (ORCID: https://orcid.org/0000-0002-3669-2964)
- Jizhong Shi
- Motomi Osato (ORCID: https://orcid.org/0000-0003-3982-9054)
- King Pan Ng (ORCID: https://orcid.org/0000-0002-0147-123X)
- Takaomi Sanda (ORCID: https://orcid.org/0000-0003-1621-4954)
- Vinay Tergaonkar (ORCID: https://orcid.org/0000-0001-9009-0844)
- Richie Soong (ORCID: https://orcid.org/0000-0002-0152-1225)
- Byrappa Venkatesh (ORCID: https://orcid.org/0000-0003-3620-0277)
- Daniel G. Tenen (ORCID: https://orcid.org/0000-0002-6423-3888)
- Dominic Chih‐Cheng Voon (ORCID: https://orcid.org/0000-0002-2963-9305)
- Julia A. Horsfield (ORCID: https://orcid.org/0000-0002-9536-7790)
- Chelsia Qiuxia Wang (ORCID: https://orcid.org/0000-0003-2471-4641)
- Brendan Pang
- Cai Ping Koh (ORCID: https://orcid.org/0000-0002-7219-1956)
- Ichiro Taniuchi (ORCID: https://orcid.org/0000-0002-9853-9068)
- Yu Shuizhou
- Avinash Govind Bahirvani (ORCID: https://orcid.org/0000-0002-7623-2823)
- Yoichi Maekawa (ORCID: https://orcid.org/0000-0002-3879-5713)
- Judith Marsman (ORCID: https://orcid.org/0000-0001-6542-3571)
- Wei‐Siang Liau (ORCID: https://orcid.org/0000-0001-8547-4712)
- Giselle Sek Suan Nah
- Shunichi Kimura
- Md Zakir Hossain (ORCID: https://orcid.org/0000-0002-6022-7835)
- Yiong Huak Chan (ORCID: https://orcid.org/0000-0002-5076-5269)
- P Y Chong
- Desmond Wai Loon Chin
- Sawako Muroi
Institutions
- Agency for Science, Technology and Research (SG)
- La Jolla Institute for Immunology (US)
- National University of Singapore (SG)
- Dunedin Public Hospital (NZ)
- National University Cancer Institute, Singapore (SG)
- Kumamoto Orthopedic Surgery Hospital (JP)
- National University Health System (SG)
- RIKEN Center for Integrative Medical Sciences (JP)
- Harvard Stem Cell Institute (US)
- Kumamoto Medical Center (JP)
- Gifu University (JP)
- Institute of Molecular and Cell Biology (SG)
- University of Otago (NZ)
- Kumamoto University (JP)
Publication Details
- Journal
- Genes to Cells
- Published
- 2025-10-19
- DOI
- https://doi.org/10.1111/gtc.70052
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Research Foundation
- Agency for Science, Technology and Research
- National Research Foundation Singapore
- Medical Research Council
- National Medical Research Council
- Japan Society for the Promotion of Science
- Institute of Molecular and Cell Biology
- Biomedical Research Council