UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Publication Date

2019-07-01

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cancer Biology | Cell Biology | Cells | Cellular and Molecular Physiology | Genetic Phenomena | Neoplasms | Pathology

Abstract

Aberrant activation of beta-catenin has been implicated in a variety of human diseases, including cancer. In spite of significant progress, the regulation of active Wnt/beta-catenin-signaling pathways is still poorly understood. In this study, we show that F-box protein 16 (FBXO16) is a putative tumor suppressor. It is a component of the SCF (SKP1-Cullin1-F-box protein) complex, which targets the nuclear beta-catenin protein to facilitate proteasomal degradation through the 26S proteasome. FBXO16 interacts physically with the C-terminal domain of beta-catenin and promotes its lysine 48-linked polyubiquitination. In addition, it inhibits epithelial-to-mesenchymal transition (EMT) by attenuating the level of beta-catenin. Therefore, depletion of FBXO16 leads to increased levels of beta-catenin, which then promotes cell invasion, tumor growth, and EMT of cancer cells. Furthermore, FBXO16 and beta-catenin share an inverse correlation of cellular expression in clinical breast cancer patient samples. In summary, we propose that FBXO16 functions as a putative tumor suppressor by forming an SCF(FBXO16) complex that targets nuclear beta-catenin in a unique manner for ubiquitination and subsequent proteasomal degradation to prevent malignancy. This work suggests a novel therapeutic strategy against human cancers related to aberrant beta-catenin activation.

Keywords

FBXO16, Wnt signaling, proteasomal degradation, tumor suppressor, β-catenin

Rights and Permissions

© 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

DOI of Published Version

10.1002/path.5252

Source

J Pathol. 2019 Jul;248(3):266-279. doi: 10.1002/path.5252. Epub 2019 Mar 8. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of pathology

Related Resources

Link to Article in PubMed

PubMed ID

30714168

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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