TTPAL promotes colorectal tumorigenesis by stabilizing TRIP6 to activate Wnt/β-catenin signaling
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AbstractCopy number alterations are crucial for the development of colorectal cancer (CRC). Our whole genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in CRC. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in CRC from a Chinese cohort (n=102), which was further validated by a TCGA cohort (n=376). High expression of TTPAL was significantly associated with shortened survival in CRC patients. TTPAL promoted cell viability and clonogenicity, accelerated cell cycle progression, inhibited cell apoptosis, increased cell migration/invasion ability in vitro, and promoted tumorigenicity and cancer metastasis in vivo. TTPAL significantly activated Wnt signaling and increased β-catenin activation and protein expression of cyclin D1 and c-Myc. Co-immunoprecipitation followed by mass spectrometry identified thyroid receptor-interacting protein 6 (TRIP6) as a direct downstream effector of TTPAL. Depletion of TRIP6 significantly abolished the effects of TTPAL on cell proliferation and Wnt activation. Direct binding of TTPAL with TRIP6 in the cytoplasm inhibited ubiquitin-mediated degradation of TRIP6; subsequently increased levels of TRIP6 displaced β-catenin from the tumor suppressor MAGI1 via competitive binding. This sequence of events allows β-catenin to enter the nucleus and promote oncogenic Wnt/β-catenin signaling. In conclusion, TTPAL is commonly overexpressed in CRC due to copy number gain, which promotes colorectal tumorigenesis by activating Wnt/β-catenin signaling via stabilization of TRIP6. TTPAL overexpression may serve as an independent new biomarker for the prognosis of CRC patients.
Acceptance Date19/04/2019
All Author(s) ListHongyan Gou, Jessie Qiaoyi Liang, Lijing Zhang, Huarong Chen, Yanquan Zhang, Rui Li, Xiaohong Wang, Jiafu Ji, Joanna HM Tong, Ka-Fai To, Joseph JY Sung, Francis KL Chan, Jing-Yuan Fang, Jun Yu
Journal nameCancer Research
Year2019
Month7
Volume Number79
Issue Number13
PublisherAmerican Association for Cancer Research
Pages3332 - 3346
ISSN0008-5472
eISSN1538-7445
LanguagesEnglish-United Kingdom

Last updated on 2020-09-07 at 04:32