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 SCF FBXO16 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.

Systematic analysis of the expression and prognosis relevance of FBXO family reveals the significance of FBXO1 in human breast cancer

“…FBXO16 interacts physically with the C-terminal domain of β-catenin and promotes its lysine 48-linked polyubiquitination and it can inhibit EMT by attenuating the level of β-catenin in BC cells [16]. This was consistent with our conclusion, the mRNA levels of FBXO16 were especially high in Luminal B subtypes and which was associated with better prognosis.…”

“…Searching of novel tumor-related molecular markers is in full swing. As new cancer biomarkers, FBXO factors dysregulation have been reported in many cancers like BC, HCC, gastric cancer, ovarian carcinoma and osteosarcoma [7,9,10,16,42]. Although several FBXO family members have been con rmed to be related to BC, their distinct molecular mechanism remains to be explored.…”

“…It inhibits EMT by attenuating the levels of β-catenin. In one sense, FBXO16 is a putative tumor suppressor that suppresses the growth, migration and invasion of multiple cancers [16]. The main function of FBXO17 is targeting glycogen synthase kinase-3β to the E3 ubiquitin ligase protein complex for polyubiquitination and proteasomal degradation [17].…”

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease

“…Functions of Fbxo16, Fbxo17, and Fbxw2 have all been linked to the regulation of the Wnt/β-catenin signaling pathway in non-muscle cells [ 153 , 154 , 155 , 156 , 157 , 158 ]. Fbxo27 was shown to direct damaged glycoproteins on the surface of lysosomes, including Lamp1 and Lamp2, towards autophagy-mediated degradation [ 159 ].…”

Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

“…A20 plays an important role in inflammation and autoimmunity, but in 2017, Lee et al demonstrated its role in TGF-β1-induced EMT and metastasis of basal-like breast cancers, through multi-monoubiquitylation of Snail1 [ 143 ]. A recent study showed that Fbxo16 also promotes the lysine 48-linked polyubiquitination of β-catenin, and its further degradation in the proteasome machinery, thus inhibiting EMT and preventing malignancy [ 89 ]. Fbxo11 also induces the ubiquitination and degradation of Snail1 in a Pkd1 phosphorylation-dependent manner, also impacting on EMT.…”