Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation

Yeong Chin Jou, Yuh Shyan Tsai, Chang Te Lin, Chun Liang Tung, Cheng Huang Shen, Hsin Tzu Tsai, Wen Horng Yang, Hung I. Chang, Syue Yi Chen, Tzong Shin Tzai

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Hypoxia-inducible factor-1α (HIF-1α) can control a transcriptional factor forkhead box P3 (Foxp3) protein expression in T lymphocyte differentiation through proteasome-mediated degradation. In this study, we unveil a reverse regulatory mechanism contributing to bladder cancer progression; Foxp3 expression attenuates HIF-1α degradation. We first demonstrated that Foxp3 expression positively correlates with the metastatic potential in T24 cells and can increase the expression of HIF-1α-target genes, such as vascular endothelial growth factor (VEGF) and glucose transporter (GLUT). Foxp3 protein can bind with HIF-1α, particularly under hypoxia. In vivo ubiquination assay demonstrated that Foxp3 can decrease HIF-1α degradation in a dose-dependent manner. Knocking-down of Foxp3 expression blocks in vivo tumor growth in mice and prolongs mice's survival, which is associated with von Willebrand factor expression. Thirty-three of 145 (22.8 %) bladder tumors exhibit Foxp3 expression. Foxp3 expression is an independent predictor for disease progression in superficial bladder cancer patients (p = 0.032), associated with less number of intratumoral CD8+ lymphocyte. The metaanalysis from 2 published datasets showed Foxp3 expression is positively associated with GLUT-4,-9, and VEGF-A, B-, D expression. This reverse post-translational regulation of HIF-1α protein by Foxp3 provides a new potential target for developing new therapeutic strategy for bladder cancer.

Original languageEnglish
Pages (from-to)65403-65417
Number of pages15
JournalOncotarget
Volume7
Issue number40
DOIs
Publication statusPublished - 2016 Jan 1

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Hypoxia-Inducible Factor 1
Ubiquitin
Urinary Bladder Neoplasms
Forkhead Transcription Factors
Gene Expression
Facilitative Glucose Transport Proteins
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor B
von Willebrand Factor
Proteasome Endopeptidase Complex
Disease Progression
Lymphocytes
T-Lymphocytes
Growth
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Jou, Yeong Chin ; Tsai, Yuh Shyan ; Lin, Chang Te ; Tung, Chun Liang ; Shen, Cheng Huang ; Tsai, Hsin Tzu ; Yang, Wen Horng ; Chang, Hung I. ; Chen, Syue Yi ; Tzai, Tzong Shin. / Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation. In: Oncotarget. 2016 ; Vol. 7, No. 40. pp. 65403-65417.
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Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation. / Jou, Yeong Chin; Tsai, Yuh Shyan; Lin, Chang Te; Tung, Chun Liang; Shen, Cheng Huang; Tsai, Hsin Tzu; Yang, Wen Horng; Chang, Hung I.; Chen, Syue Yi; Tzai, Tzong Shin.

In: Oncotarget, Vol. 7, No. 40, 01.01.2016, p. 65403-65417.

Research output: Contribution to journalArticle

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