RESUMO
PRMT1 plays a vital role in breast tumorigenesis; however, the underlying molecular mechanisms remain incompletely understood. Herein, we show that PRMT1 plays a critical role in RNA alternative splicing, with a preference for exon inclusion. PRMT1 methylome profiling identifies that PRMT1 methylates the splicing factor SRSF1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and exon inclusion. In breast tumors, PRMT1 overexpression is associated with increased SRSF1 arginine methylation and aberrant exon inclusion, which are critical for breast cancer cell growth. In addition, we identify a selective PRMT1 inhibitor, iPRMT1, which potently inhibits PRMT1-mediated SRSF1 methylation, exon inclusion, and breast cancer cell growth. Combination treatment with iPRMT1 and inhibitors targeting SRSF1 phosphorylation exhibits an additive effect of suppressing breast cancer cell growth. In conclusion, our study dissects a mechanism underlying PRMT1-mediated RNA alternative splicing. Thus, PRMT1 has great potential as a therapeutic target in breast cancer treatment.
Assuntos
Processamento Alternativo , Neoplasias da Mama , Humanos , Feminino , Metilação , Processamento Alternativo/genética , Transformação Celular Neoplásica/genética , RNA/metabolismo , Neoplasias da Mama/genética , Éxons/genética , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
Quinolinic acid (QA) is an index for some diseases, whose detection is of importance. This work presents a samarium metal-organic framework (Sm-MOF) containing 5-sulfoisophthalate ligand (SIP3-). The fluorescence of Sm-MOF integrates the emission at 339 nm from the SIP3- ligand and four characteristic 4G5/2 â 4Hj (j = 5/2, 7/2, 9/2, and 11/2) transitions at 559, 596, 642, and 701 nm from Sm(III). Sm-MOF as a turn-off fluorescence sensor to QA exhibits high sensitivity, selectivity, and durability. The fluorescence quenching response to QA shows a linear relationship of I0/I = 0.00496·CQA + 1.12474 in the QA concentration of 0-500 µM and a limit of detection calculated as 4.11 µM. Sm-MOF shows the structural and fluorescent stabilities in five quenching-recovery cycles. The recoveries of close to 100% in human urine and serum indicate high reliability. The paper-based Sm-MOF sensor displays a rough QA quantitative analysis by recognizing red values in the on-site QA detection.
