TELO2-interacting protein 1 (TTI1), a novel Wnt/β-catenin target gene, decreases chemo-sensitivity in colorectal cancer by modulating DNA damage responses
- Mol Biomed. 2026 Jun 12;7(1):88. doi: 10.1186/s43556-026-00475-8.
- 1. Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 2. Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 3. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 4. Hengyang Medical School, The First Affiliated Hospital, Cancer Research Institute, University of South China, Hengyang, Hunan, China.
- 5. Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 6. Department of Gastrointestinal Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 7. Department of Nutrition and Health, China Agricultural University, Beijing, China.
- 8. Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
- 9. Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
- 10. MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha, Hunan, China. [email protected].
- 11. National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China. [email protected].
- 12. Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
- # Contributed equally.
Colorectal Cancer is frequently driven by hyperactivation of Wnt/β-catenin signaling, which also contributes to reduced responsiveness to chemotherapy. However, how aberrant Wnt/β-catenin signaling enables colorectal Cancer cells to tolerate chemotherapy-induced DNA damage remains elusive. Identifying actionable downstream effectors of this pathway may provide a more selective strategy to improve chemotherapy response while avoiding the toxicity associated with global Wnt inhibition. Here we show that TELO2-interacting protein 1 (TTI1) is a direct transcriptional target of β-catenin/TCF in colorectal Cancer. TTI1 expression correlates with β-catenin abundance and is elevated in tumors from patients with poor response to neoadjuvant chemotherapy. Mechanistically, TTI1 maintains the integrity of the TELO2-TTI1-TTI2 complex and stabilizes the DNA damage response kinases ATM and ATR. Genetic depletion of TTI1 destabilizes ATM and ATR, attenuates DNA damage signaling, impairs double-strand break repair, and sensitizes colorectal Cancer cells to 5-fluorouracil and oxaliplatin. Conversely, restoration of TTI1 or ATM/ATR re-establishes DNA damage responses and chemo-insensitivity. Pharmacological suppression of the TTT complex by piperlongumine mimics TTI1 loss and enhances the anti-tumor activity of chemotherapy in cell lines, xenografts, Apc-mutant patient-derived organoids and APCmin/+ colonic adenomas. These findings define a β-catenin-TTI1-ATM/ATR axis that links Wnt/β-catenin activation to DNA damage tolerance and chemotherapy response in colorectal Cancer. Targeting TTI1 is therefore a promising approach to improve chemotherapy efficacy in Wnt/β-catenin-activated colorectal Cancer.