F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear β-catenin function.

Abstract

Aberrant activation of β-catenin has been implicated in a variety of human diseases, including cancer. In spite of significant progress, the regulation of active Wnt/β-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 β-catenin protein to facilitate proteasomal degradation through the 26S proteasome. FBXO16 interacts physically with the C-terminal domain of β-catenin and promotes its lysine 48-linked polyubiquitination. In addition, it inhibits epithelial-to-mesenchymal transition (EMT) by attenuating the level of β-catenin. Therefore, depletion of FBXO16 leads to increased levels of β-catenin, which then promotes cell invasion, tumor growth, and EMT of cancer cells. Furthermore, FBXO16 and β-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 SCFFBXO16 complex that targets nuclear β-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 β-catenin activation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

• Authors: Debasish Paul, Sehbanul Islam, Rajesh Kumar Manne, U S Dinesh, Sunil K Malonia, Biswanath Maity, Ramanamurthy Boppana, Srikanth Rapole, Praveen Kumar Shetty, Manas Kumar Santra
• Journal: The Journal of pathology (J Pathol) Vol. 248 Issue 3 Pg. 266-279 (07 2019) ISSN: 1096-9896 [Electronic] England
• PMID: 30714168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Chemical References

• CTNNB1 protein, human
• F-Box Proteins
• FBXO16 protein, human
• Nuclear Proteins
• beta Catenin

Topics

• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Epithelial-Mesenchymal Transition (genetics)
• F-Box Proteins (metabolism)
• Gene Expression Regulation, Neoplastic (genetics)
• Genes, Tumor Suppressor (physiology)
• Humans
• Nuclear Proteins (metabolism)
• Wnt Signaling Pathway (physiology)
• beta Catenin (metabolism)