Inhibition of FOXO3 tumor suppressor function by betaTrCP1 through ubiquitin-mediated degradation in a tumor mouse model.
BACKGROUND
The ubiquitin-proteasome system is the primary proteolysis machine for controlling protein stability of the majority of regulatory proteins including those that are critical for cancer development. The forkhead box transcription factor FOXO3 plays a key role in regulating tumor suppression; however, the control of FOXO3 protein stability remains to be established. It is crucial to elucidate the molecular mechanisms underlying the ubiquitin-mediated degradation of FOXO3 tumor suppressor.


RESULTS
Here we show that betaTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkappaB kinase-beta phosphorylation dependent manner. Silencing betaTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing betaTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing betaTrCP1 promotes tumorigenesis and tumor growth in vivo.


CONCLUSIONS
This is a unique demonstration that the betaTrCP1-mediated FOXO3 degradation plays a crucial role in tumorigenesis. These findings significantly contribute to understanding of the control of FOXO3 stability in cancer cells and may provide opportunities for developing innovative anticancer therapeutic modalities.
Tsai
Wen-Bin
WB
Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
Chung
Young Min
YM
Zou
Yiyu
Y
Park
See-Hyoung
SH
Xu
Zhaohui
Z
Nakayama
Keiko
K
Lin
Sue-Hwa
SH
Hu
Mickey C-T
MC
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
C471644:BTRC protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins