title: PRMT6 increases cytoplasmic localization of p21CDKN1A in cancer cells through arginine methylation and makes more resistant to cytotoxic agents.
abstract: p21(CDKN1A) is known as a potent inhibitor of cyclin-dependent kinase (CDK), which regulates cell cycle in response to various stimuli, including DNA damage, on the p53-dependent manner. Here we demonstrate that protein arginine methyltransferase 6 (PRMT6) methylates p21 at arginine 156 and promotes phosphorylation of threonine 145 on p21, resulting in the increase of cytoplasmic localization of p21. The cytoplasmic presence of p21 makes cancer cells more resistant to cytotoxic agents. Our results indicate that PRMT6 appears to be one of the key proteins to dysregulate p21 functions in human cancer, and targeting this pathway may be an appropriate strategy for development of anticancer drugs.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115, Chicago, IL 60637, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakakido
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115, Chicago, IL 60637, USA.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Dohmae
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115, Chicago, IL 60637, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115, Chicago, IL 60637, USA.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001120:Arginine; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013912:Threonine; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D013912:Threonine; D004317:Doxorubicin; D001120:Arginine; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: PRMT6; arginine methylation; cancer chemoresistance; p21CDKN1A; subcellular localization