title: p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6.
abstract: p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence. Consistent with this role, p21 is a downstream target of several tumour suppressors and oncogenes, and it is downregulated in the majority of tumours, including breast cancer. Here, we report that protein arginine methyltransferase 6 (PRMT6), a type I PRMT known to act as a transcriptional cofactor, directly represses the p21 promoter. PRMT6 knock-down (KD) results in a p21 derepression in breast cancer cells, which is p53-independent, and leads to cell cycle arrest, cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency (SCID) mice for all the cancer lines examined. We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence, and it restores their ability to grow on soft agar. We conclude that PRMT6 acts as an oncogene in breast cancer cells, promoting growth and preventing senescence, making it an attractive target for cancer therapy.
authors.affiliation: Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore 138673.
authors.forename: Sameer
authors.initials: S
authors.lastname: Phalke
authors.forename: Slim
authors.initials: S
authors.lastname: Mzoughi
authors.forename: Marco
authors.initials: M
authors.lastname: Bezzi
authors.forename: Nancy
authors.initials: N
authors.lastname: Jennifer
authors.forename: Wei Chuen
authors.initials: WC
authors.lastname: Mok
authors.forename: Diana H P
authors.initials: DH
authors.lastname: Low
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Thike
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Kuznetsov
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.forename: P Mathijs
authors.initials: PM
authors.lastname: Voorhoeve
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases