PRMT6 increases cytoplasmic localization of p21CDKN1A in cancer cells through arginine methylation and makes more resistant to cytotoxic agents

// Makoto Nakakido 1, * , Zhenzhong Deng 1, * , Takehiro Suzuki 2 , Naoshi Dohmae 2 , Yusuke Nakamura 1 , Ryuji Hamamoto 1 1 Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115, Chicago, IL 60637, USA 2 Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama 351–0198, Japan * These authors have contributed equally to this work Correspondence to: Ryuji Hamamoto, e-mail: rhamamoto@medicine.bsd.uchicago.edu Keywords: p21 CDKN1A , arginine methylation, PRMT6, subcellular localization, cancer chemoresistance Received: July 08, 2015      Accepted: August 12, 2015      Published: September 03, 2015 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.