ArticleProceedings of the National Academy of Sciences of the United States of America2019
The FBXW2-MSX2-SOX2 axis regulates stem cell property and drug resistance of cancer cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 97 citations in OpenAlex.
- Protein neddylation as a therapeutic target: challenges and opportunities.The Journal of clinical investigation · 2026Review
- Roles of Msx2 in exogen control: modulating the stem cell niche during the transition from hair shedding to regeneration.Journal of advanced research · 2026Article
- A Stretchable, Transparent, Photothermally Stimulated Laser-Induced Graphene Patch for Noninvasive Skin Tumor Treatment.ACS nano · 2026Article
- SOX2 is a dispensable modulator of NUT carcinoma oncogenesis in mice.Life science alliance · 2026Article
- Gene regulatory network transitions reveal the central transcription factors in lung adenocarcinoma progression.NPJ systems biology and applications · 2026Article
- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- SOX2 Is a Potential Diagnostic Biomarker and Anticancer Target in Cutaneous Squamous Cell Carcinoma in Dystrophic Epidermolysis Bullosa: A Case Series Study.JID innovations : skin science from molecules to population health · 2026Article
- Neddylation related gene signature for prognostic biomarkers in colorectal cancer with integrated bioinformatics and experimental analysis.Discover oncology · 2025Article
- F-box proteins in cancer: from cancer cells to the tumor microenvironment.Cell communication and signaling : CCS · 2025Review
- VRK2 targeting potentiates anti-PD-1 immunotherapy in hepatocellular carcinoma through MYC destabilization.Nature communications · 2025Article
- The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells.Neoplasia (New York, N.Y.) · 2025Article
- Signaling pathways as the pivotal regulators of cisplatin resistance in tumor cells through SOX2 upregulation.Medical oncology (Northwood, London, England) · 2025Review
- FOXP2 suppresses gastric cancer progression by transcriptionally repressing FBXW2 via WASL degradation.Cell death discovery · 2025Article
- Article
- Expression of Elastin, F-Box and WD-40 Domain-Containing Protein 2, Fibrillin-1, and Alpha-Smooth Muscle Actin in Utilized Blood Vessels for explant culture-A New 3D in Vitro Vascular Model from Bovine Legs.Cell biochemistry and biophysics · 2025Article
- Key roles of ubiquitination in regulating critical regulators of cancer stem cell functionality.Genes & diseases · 2025Review
- AKT1 as a therapeutic target for platinum-resistant SOX2 positive ovarian cancer cells.Scientific reports · 2025Article
- F-box in breast cancer: mechanism of action and therapeutic potential.American journal of translational research · 2025Review
- TREMSUCS-TCGA - an integrated workflow for the identification of biomarkers for treatment success.Journal of integrative bioinformatics · 2024Article
- Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer.Cell communication and signaling : CCS · 2024Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression. Mechanistic characterization revealed that MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds to MSX2 and promotes MSX2 ubiquitylation and degradation. Likewise, FBXW2 overexpression shortens the protein half-life of MSX2, whereas FBXW2 knockdown extends it. We further identified hypoxia as a stress condition that induces VRK2 kinase to facilitate MSX2-FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. Biologically, expression of FBXW2 or SOX2 promotes tumor sphere formation, which is blocked by MSX2 expression. By down-regulating SOX2 through inactivation of FBXW2 E3 ligase, MLN4924 sensitizes breast cancer cells to tamoxifen in both in vitro and in vivo cancer cell models. Thus, a negative cascade of the FBXW2-MSX2-SOX2 axis was established, which regulates stem cell property and drug resistance. Finally, an inverse correlation of expression was found between FBXW2 and MSX2 in lung and breast cancer tissues. Collectively, our study revealed an anticancer mechanism of MLN4924. By inactivating FBXW2, MLN4924 caused MSX2 accumulation to repress SOX2 expression, leading to suppression of stem cell property and sensitization of breast cancer cells to tamoxifen.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.