PUBLICATION
TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
- Authors
- Aripaka, K., Gudey, S.K., Zang, G., Schmidt, A., Åhrling, S.S., Österman, L., Bergh, A., von Hofsten, J., Landström, M.
- ID
- ZDB-PUB-190703-2
- Date
- 2019
- Source
- EBioMedicine 45: 192-207 (Journal)
- Registered Authors
- von Hofsten, Jonas
- Keywords
- LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish, β-Catenin
- MeSH Terms
-
- Animals
- CRISPR-Cas Systems/genetics
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation/genetics*
- Inflammation/pathology
- Low Density Lipoprotein Receptor-Related Protein-5/genetics
- Male
- Prostatic Neoplasms/genetics*
- Prostatic Neoplasms/pathology
- TNF Receptor-Associated Factor 6/genetics*
- Wnt Signaling Pathway/genetics
- Wnt3A Protein/genetics*
- Zebrafish
- Zebrafish Proteins/genetics*
- beta Catenin/genetics
- PubMed
- 31262711 Full text @ EBioMedicine
Citation
Aripaka, K., Gudey, S.K., Zang, G., Schmidt, A., Åhrling, S.S., Österman, L., Bergh, A., von Hofsten, J., Landström, M. (2019) TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer. EBioMedicine. 45:192-207.
Abstract
Background Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.
Methods TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.
Findings Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.
Interpretation We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression. FUND: KAW 2012.0090, CAN 2017/544, Swedish Medical Research Council (2016-02513), Prostatacancerförbundet, Konung Gustaf V:s Frimurarestiftelse and Cancerforskningsfonden Norrland. The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping