Protein arginine-methyltransferase-dependent oncogenesis.
Enzymes that mediate reversible epigenetic modifications have not only been recognized as key in regulating gene expression and oncogenesis, but also provide potential targets for molecular therapy. Although the methylation of arginine 3 of histone 4 (H4R3) by protein arginine methyltransferase 1 (PRMT1) is a critical modification for active chromatin and prevention of heterochromatin spread, there has been no direct evidence of any role of PRMTs in cancer. Here, we show that PRMT1 is an essential component of a novel Mixed Lineage Leukaemia (MLL) oncogenic transcriptional complex with both histone acetylation and H4R3 methylation activities, which also correlate with the expression of critical MLL downstream targets. Direct fusion of MLL with PRMT1 or Sam68, a bridging molecule in the complex for PRMT1 interaction, could enhance self-renewal of primary haematopoietic cells. Conversely, specific knockdown of PRMT1 or Sam68 expression suppressed MLL-mediated transformation. This study not only functionally dissects the oncogenic transcriptional machinery associated with an MLL fusion complex, but also uncovers--for the first time--an essential function of PRMTs in oncogenesis and reveals their potential as novel therapeutic targets in human cancer.
Cheung
Ngai
N
Haemato-Oncology Section, The Institute of Cancer Research, Sutton, Greater London SM2 5NG, UK.
Chan
Li Chong
LC
Thompson
Alex
A
Cleary
Michael L
ML
So
Chi Wai Eric
CW
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008745:Methylation; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; C489559:KHDRBS1 protein, human; D016601:RNA-Binding Proteins; C097899:homeobox protein HOXA9; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases