ArticleProceedings of the National Academy of Sciences of the United States of America2019
LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity.
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 47 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
47 citing papers in PubMed, 73 citations in OpenAlex.
- Protist oxygen-sensing and the role of prolyl hydroxylase-regulation of E3(SCF) ubiquitin ligases.Biochimica et biophysica acta. General subjects · 2026Review
- Finely-tuned regulator of DNA repair: FBXW7-185aa may modulate glioblastoma radiosensitization and the tumor immune microenvironment.Translational oncology · 2026Article
- FBXW7 Targets the SPT6-ΔNp63 Axis for Degradation to Inhibit Esophageal Tumorigenesis Induced by 4-Nitroquinoline N-Oxide.MedComm · 2026Article
- Canonical and Non-Canonical Functions of Histone H3K4 Methylation Modifiers in Cancer.Cancer science · 2025Review
- Discovery of LD-110 as an Effective LSD1 PROTAC Degrader for the Treatment of Esophagus Squamous Cancer.Journal of medicinal chemistry · 2025Article
- The FBXW7-KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Calcineurin-mediated dephosphorylation stabilizes E2F1 protein by suppressing binding of the FBXW7 ubiquitin ligase subunit.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Wee1 inhibitor PD0166285 sensitized TP53 mutant lung squamous cell carcinoma to cisplatin via STAT1.Cancer cell international · 2024Article
- The scaffolding function of LSD1 controls DNA methylation in mouse ESCs.Nature communications · 2024Article
- Molecular insights and clinical implications for the tumor suppressor role of SCFBiochimica et biophysica acta. Reviews on cancer · 2024Review
- PHF2 regulates genome topology and DNA replication in neural stem cells via cohesin.Nucleic acids research · 2024Article
- To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families.International journal of molecular sciences · 2024Review
- FBXW7 in gastrointestinal cancers: from molecular mechanisms to therapeutic prospects.Frontiers in pharmacology · 2024Review
- E3-ubiquitin ligase, FBXW7 regulates mitotic progression by targeting BubR1 for ubiquitin-mediated degradation.Cellular and molecular life sciences : CMLS · 2023Article
- Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51.Nature communications · 2023Article
- Somatic gain-of-function mutations in BUD13 promote oncogenesis by disrupting Fbw7 function.The Journal of experimental medicine · 2023Article
- FBXW7 in breast cancer: mechanism of action and therapeutic potential.Journal of experimental & clinical cancer research : CR · 2023Review
- Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition.Nature communications · 2023Article
- LSD1: an emerging face in altering the tumor microenvironment and enhancing immune checkpoint therapy.Journal of biomedical science · 2023Review
- Insights from a Computational-Based Approach for Analyzing Autophagy Genes across Human Cancers.Genes · 2023Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
FBXW7 acts as a typical tumor suppressor, with loss-of-function alterations in human cancers, by promoting ubiquitylation and degradation of many oncoproteins. Lysine-specific demethylase 1 (LSD1) is a well-characterized histone demethylase. Whether LSD1 has demethylase-independent activity remains elusive. Here we report that LSD1 directly binds to FBXW7 to destabilize FBXW7 independent of its demethylase activity. Specifically, LSD1 is a pseudosubstrate of FBXW7 and LSD1-FBXW7 binding does not trigger LSD1 ubiquitylation, but instead promotes FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. The self-ubiquitylated FBXW7 is subjected to degradation by proteasome as well as lysosome in a manner dependent on autophagy protein p62/SQSTM1. Biologically, LSD1 destabilizes FBXW7 to abrogate its functions in growth suppression, nonhomologous end-joining repair, and radioprotection. Collectively, our study revealed a previously unknown activity of LSD1, which likely contributes to its oncogenic function. Targeting LSD1 protein, not only its demethylase activity, might be a unique approach for LSD1-based drug discovery for anticancer application.
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Registered trials
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 OpenQuestion graph.