Jul 2026· Cancer Science· 0 citations· 66 references
Medicine
TL;DR
By critically appraising its substrate diversity and functional versatility, it is proposed that FBXO11 be regarded not merely as a straightforward therapeutic target, but rather as a prognostic biomarker and a context‐specific vulnerability that necessitates precision medicine strategies for effective clinical intervention.
Abstract
ABSTRACT F‐box protein 11 (FBXO11), a critical component of the F‐box protein family, serves as the substrate recognition subunit of the Skp1‐Cul1‐F‐box (SCF) E3 ubiquitin ligase complex, orchestrates the ubiquitination and proteasomal degradation of a diverse array of substrates, thereby regulating various physiological and pathological processes. Emerging evidence reveals that FBXO11 is aberrantly expressed in multiple tumor types. Predominantly, FBXO11 functions as a potent tumor suppressor, and its downregulation is strongly correlated with tumor initiation, aggressive progression, and poor prognoses. Mechanistically, FBXO11 deficiency facilitates tumor development and metastasis by deregulating the cell cycle progression, enhancing cell migration and invasion, and driving epithelial‐mesenchymal transition (EMT). However, the broad substrate spectrum of FBXO11 dictates its context‐dependent roles in cancer biology, imparting significant challenges to its direct therapeutic targeting, as systemic modulation may yield unpredictable off‐target or paradoxical effects. This review provides a comprehensive overview of current understanding of FBXO11 in oncology. By critically appraising its substrate diversity and functional versatility, we aim to re‐evaluate the clinical translation of FBXO11, proposing that it be regarded not merely as a straightforward therapeutic target, but rather as a prognostic biomarker and a context‐specific vulnerability that necessitates precision medicine strategies for effective clinical intervention.
Emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment and immunotherapy response, positioning it as an increasingly attractive target for intervention.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations
This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword, and comprehensively evaluates the landscape of emerging USP2 inhibitors.
Peng Hao, Jiale Wan, Zhangyu Guo et al.· Biochimica et biophysica act...· 0 citations
A review of the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery highlights its potential as a therapeutic target for precision medicine.
Tongyong Luo, Shuncai Wu, Qing-Song Wang et al.· Frontiers in Immunology· 1 citation
ABSTRACT Epithelial‐mesenchymal transition (EMT) is a key driver of breast cancer progression, yet the upstream transcriptional and ubiquitin‐mediated mechanisms that modulate Hippo signaling remain incompletely defined. In this study, we identify a regulatory axis in which the transcription factor ZBTB11 promotes breast cancer aggressiveness by enhancing the expression of the F‐box protein FBXO28. ZBTB11 directly binds to the FBXO28 promoter and increases its transcription, leading to elevated FBXO28 protein levels. We show that FBXO28 functions as an E3 ubiquitin ligase that targets the core Hippo kinase MST1 for K48‐linked ubiquitination and proteasomal degradation. Reduction of MST1 diminishes Hippo pathway activity, resulting in decreased phosphorylation and enhanced nuclear accumulation of Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ), which subsequently activates EMT‐related gene expression. Functionally, disruption of the ZBTB11‐FBXO28‐MST1 axis suppresses EMT, migration, invasion, and tumor growth in vitro and in vivo, whereas reintroduction of FBXO28 or depletion of MST1 reverses these effects. Together, our findings reveal a previously unrecognized transcription‐ubiquitination cascade that modulates Hippo signaling and contributes to breast cancer progression, highlighting this axis as a candidate therapeutic vulnerability that warrants further validation for limiting metastasis.
An Xu, Xiang-nan Xu, Xiao Huang et al.· Advancement of science· 0 citations
Rnd3 is an atypical member of the Rho GTPase family whose activity is mainly regulated by expression, localization and protein stability rather than canonical GDP/GTP cycling. In cancer, Rnd3 has been described both as a tumor suppressor and as a tumor-promoting factor, creating an apparent functional paradox. We propose that this paradox is resolved by a mechanistic invariant: Rnd3 exerts a conserved inhibition of RhoA/ROCK1-dependent actomyosin contractility, whose phenotypic output is redirected by context-specific accessory effectors rather than reversed. In this review, we revisit this paradox by integrating evidence from mechanistic studies, tumor models and patient-associated datasets. We propose that Rnd3 should not be interpreted through a binary oncogene/tumor-suppressor framework, but rather as a context-dependent regulator of tumor cell state. In many tumor settings, Rnd3 repression or loss of Rnd3 function favors proliferation, apoptosis resistance and therapy resistance through pathways involving Notch, NF-κB, EGFR/ERK, EZH2-dependent chromatin regulation, m6A-mediated RNA control, microRNAs and chaperone-mediated autophagy. However, in selected contexts, including RTK-driven glioblastoma, hepatocellular carcinoma, non-small-cell lung cancer, melanoma and gastric cancer, Rnd3 may support tumor fitness, migration or invasive plasticity. We therefore propose a functional stratification model in which Rnd3 output depends on the biological process, tumor lineage, pathway activity and mechanical state of the cell.
Elisa Lledó, Olga Gómez, Alexandra Bizy et al.· Cells· 0 citations
Flap endonuclease 1 (FEN1), a key enzyme in DNA metabolism, exhibits oncogenic properties in various cancers. However, its functional role and underlying mechanisms in lung adenocarcinoma (LUAD) progression and tumor immunity remain poorly defined. Here, we demonstrate that FEN1 is significantly upregulated in LUAD tissues and serves as an independent prognostic factor for poor survival. Genetic depletion of FEN1 suppressed LUAD cell proliferation by inducing G0/G1 cell cycle arrest and cellular senescence, while significantly impairing migration and invasion capabilities. Mechanistically, integrated proteomic and molecular analyses revealed that FEN1 knockdown disrupts the carboxyl-terminal subunit of mucin 1 (MUC1-C)/PI3K/AKT autoregulatory loop, a critical driver of oncogenic signaling. Furthermore, FEN1 downregulation inhibited the MUC1-C/p65/ programmed death-ligand 1 (PD-L1) signaling axis, thereby alleviating tumor-mediated immunosuppression. This was evidenced by enhanced antitumor immunity, characterized by the local expansion of CD4
+
T cells and restored effector function of CD8
+
T cells, both in vitro and in vivo. Mechanistically, independent of its nuclease activity, FEN1 interacts with the N-terminus of eukaryotic translation initiation factor 4A3 (EIF4A3) to facilitate its binding to MUC1-C mRNA. Specifically, FEN1 is required for EIF4A3-mediated maintenance of both the transcript stability and translation efficiency of MUC1-C. Clinically, FEN1, MUC1-C, and PD-L1 are coordinately upregulated in LUAD tissues, and their co-expression predicts poor patient survival irrespective of EGFR mutation status. Our findings establish the FEN1/EIF4A3/MUC1-C axis as a novel mechanism driving LUAD progression by concurrently regulating intrinsic malignancy and extrinsic immune evasion, presenting FEN1 targeting as a promising dual-hit therapeutic strategy.
Min Wu, Ben-Meng Wu, Xue-Bing Yan et al.· Cell Death & Disease· 0 citations
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