TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling.

Abstract:

:Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal cancer from a Chinese cohort (n = 102), which was further validated by a The Cancer Genome Atlas (TCGA) cohort (n = 376). High expression of TTPAL was significantly associated with shortened survival in patients with colorectal cancer. 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. Coimmunoprecipitation 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 and, 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 promotes oncogenic Wnt/β-catenin signaling. In conclusion, TTPAL is commonly overexpressed in colorectal cancer 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 patients with colorectal cancer. SIGNIFICANCE: TTPAL, a gene preferentially amplified in colorectal cancer, promotes colon tumorigenesis via activation of the Wnt/β-catenin pathway.

journal_name

Cancer Res

journal_title

Cancer research

authors

Gou H,Liang JQ,Zhang L,Chen H,Zhang Y,Li R,Wang X,Ji J,Tong JH,To KF,Sung JJY,Chan FKL,Fang JY,Yu J

doi

10.1158/0008-5472.CAN-18-2986

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

3332-3346

issue

13

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-18-2986

journal_volume

79

pub_type

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