Abstract
The Wnt/β-catenin signaling pathway has emerged as a key regulator of complex biological processes, such as embryonic development, cell proliferation, cell fate decision and tumorigenesis. Recent studies have shown that the deregulation of Wnt/β-catenin signaling is frequently observed and leads to abnormal cell growth in human breast cancer cells. In this study, we identified a novel regulatory mechanism of Wnt/β-catenin signaling through RARRES3 that targets and modulates the acylation status of Wnt proteins and co-receptor low-density lipoprotein receptor-related protein 6, resulting in the suppression of epithelial–mesenchymal transition and cancer stem cell properties. Mutation of the conserved active site residues of RARRES3 indicates that RARRES3 serves as an acyl protein thioesterase that tethers its target proteins and modulates their acylation status. Furthermore, the functions of p53 in cell proliferation and Wnt/β-catenin signaling are significantly associated with the induction of RARRES3. Thus our findings provide a new insight into the molecular link between p53, protein acylation and Wnt/β-catenin signaling whereby RARRES3 plays a pivotal role in modulating the acylation status of signaling proteins.
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Abbreviations
- RARRES3:
-
retinoic acid receptor responder 3
- TICs:
-
tumor-initiating cells
- EMT:
-
epithelial–mesenchymal transition
- LRP6:
-
lipoprotein receptor-related protein 6
- PI3K:
-
phosphatidylinositol 3-kinase
- MAPK:
-
mitogen-activated protein kinase
- ERK1/2:
-
extracellular signal-regulated kinase 1/2
- EGFR:
-
epidermal growth factor receptor
- ABE:
-
acyl biotinyl exchange
- sFRP1:
-
secreted Frizzled-related protein 1
- Dkk1:
-
dickkopf-related protein 1
- JNK:
-
c-Jun N-terminal kinases
- 5-FU:
-
5-fluorouracil
- MDA and MCF:
-
control vector transfected MDA-MB 231 and MCF-7 cells
- R-MDA and R-MCF:
-
RARRES3-overexpressing cells
- shC-MDA and shC-MCF:
-
controlled virus-infected MDA-MB 231 and MCF-7 cell lines
- shR-MDA and shR-MCF:
-
RARRES3 knockdown cell lines
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Acknowledgements
This work was supported by Grants from the National Science Council (NSC-97-2320-B-016-003-MY3, NSC 100-2320-B-016-007 and NSC 101-2320-B-016-010-MY2 to T-C.C.) and the Ministryof National Defense (DOD-100-C-05-04, MAB-101-48 and MAB-102-9 to T-CC), Taipei, Taiwan, ROC. We are also grateful to Nuliv Science Co., Taipei, Taiwan, ROC, for support of this work.
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Hsu, TH., Jiang, SY., Chan, WL. et al. Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells. Cell Death Differ 22, 801–814 (2015). https://doi.org/10.1038/cdd.2014.175
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DOI: https://doi.org/10.1038/cdd.2014.175
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