Yes1-mediated Cul9 phosphorylation promotes the metabolic reprogramming in gastric cancer
Wu, Y.; Zhang, H.; Zhang, S.; Wang, M.; Wang, H.; Huang, H.; Hong, X.; Zhang, Z.; Li, Y.
Show abstract
Although Cul9 has been implicated in human carcinogenesis, its upstream regulators and roles remain unknown. Herein, we indicate that the Cul9 promoter is hypermethylated in GCs. Bioinformatics, mass spectrometry, and unbiased-kinase screen identify the tyrosine kinase Yes1 as a key regulator of Cul9. Yes1 phosphorylates Cul9 at Y1505, promoting its selective autophagy. Patient-associated mutation of Yes1 or helicobacter pylori infection induces Cul9-Y1505 phosphorylation which switches Cul9 from a tumor-suppressor to an oncogene, as evidenced by the fact that Cul9-Y1505D knockin mice are more susceptible to gastric tumorigenesis than wild-type counterparts. Metabolic profiling and ATAC sequencing reveal that Cul9-Y1505D mutant promotes pyrimidine and purine synthesis pathways in GC. DNA-demethylating drug decitabine or HG78 compound upregulates Cul9 expression and limits GC cell proliferation in a Yes1-dependent manner. The Yes1 inhibitor CH6953755 or Leflunomide and Mycophenolate mofetil (MMF) also impair the malignancy of GC with Cul9 dysregulation. Cul9 in turn binds Yes1 and disrupts Yes1 stability, establishing a feedback circuit. Collectively, our project reveals an unrecognized role of the Yes1-Cul9 loop in GC, suggesting potential therapeutic targets.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Super-Enhancer Driven ZFP36L1 Promotes PD-L1 Expression in Infiltrative Gastric Cancer 97%
- Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway 96%
- Targeting SLC7A11-mediated cysteine metabolism for the treatment of trastuzumab resistant HER2 positive breast cancer 95%
Similar papers in this journal
- Rigosertib promotes anti-tumor immunity via autophagic degradation of PD-L1 in colorectal cancer cells 95%
- UDP-Glucose 6-Dehydrogenase Knockout Impairs Migration and Decreases in vivo Metastatic Ability of Breast Cancer Cells 93%
- Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase 93%
Similar papers in this journal
- USP28 enables oncogenic transformation of respiratory cells and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K. 93%
- Targeting the cell and non-cell autonomous regulation of 47S synthesis by GCN2 in colon cancer. 93%
- Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion 93%
Similar papers in this journal
- PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer 94%
- Androgen Receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR 94%
- Identification of Raptor and GLI1 as USP37 substrates highlight its context-specific function in medulloblastoma cells. 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.