RRC ID 72009
Author Meng Q, Lu YX, Wei C, Wang ZX, Lin JF, Liao K, Luo XJ, Yu K, Han Y, Li JJ, Tan YT, Li H, Zeng ZL, Li B, Xu RH, Ju HQ.
Title Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis.
Journal Oncogene
Abstract Metastasis accounts for the major cause of cancer-related mortality. How disseminated tumor cells survive under suspension conditions and avoid anoikis is largely unknown. Here, using a metabolic enzyme-centered CRISPR-Cas9 genetic screen, we identified methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) as a novel suppressor of anoikis. MTHFD1 depletion obviously restrained the capacity of cellular antioxidant defense and inhibited tumor distant metastasis. Mechanistically, MTHFD1 was found to bind the protein arginine methyltransferase 5 (PRMT5) and then undergo symmetric dimethylation on R173 by PRMT5. Under suspension conditions, the interaction between MTHFD1 and PRMT5 was strengthened, which increased the symmetric dimethylation of MTHFD1. The elevated methylation of MTHFD1 largely augmented its metabolic activity to generate NADPH, therefore leading to anoikis resistance and distant organ metastasis. Therapeutically, genetic depletion or pharmacological inhibition of PRMT5 declined tumor distant metastasis. And R173 symmetric dimethylation status was associated with metastasis and prognosis of ESCC patients. In conclusion, our study uncovered a novel regulatory role and therapeutic implications of PRMT5/MTHFD1 axis in facilitating anoikis resistance and cancer metastasis.
Volume 41(32)
Pages 3912-3924
Published 2022-8-1
DOI 10.1038/s41388-022-02387-7
PII 10.1038/s41388-022-02387-7
PMID 35798877
MeSH Anoikis / genetics Arginine / genetics Arginine / metabolism Formate-Tetrahydrofolate Ligase* / metabolism Humans Methylation Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism Minor Histocompatibility Antigens / metabolism Neoplasms* / genetics Protein-Arginine N-Methyltransferases / metabolism
IF 7.971
Human and Animal Cells TE-11(RCB2100)