Cancer-related transcription regulator protein NAC1 forms a protein complex with CARM1 for ovarian cancer progression

// Naomi Nakayama 1 , Gyosuke Sakashita 1 , Yuko Nariai 1 , Hiroaki Kato 1 , Kaori Sinmyozu 3, 5 , Jun-ichi Nakayama 4 , Satoru Kyo 2 , Takeshi Urano 1 and Kentaro Nakayama 2 1 Department of Biochemistry, Shimane University School of Medicine, Izumo, Japan 2 Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Japan 3 Proteomics Support Unit, RIKEN Center for Developmental Biology, Kobe, Japan 4 Graduate School of Natural Sciences, Nagoya City University, Nagoya, Japan 5 Current address: National Cerebral and Cardiovascular Center, Osaka, Japan Correspondence to: Kentaro Nakayama, email: kn88@med.shimane-u.ac.jp Takeshi Urano, email: turano@med.shimane-u.ac.jp Keywords: nucleus accumbens-associated protein 1 (NAC1); coactivator-associated arginine methyltransferase 1 (CARM1); protein arginine N-methyltransferase 4 (PRMT4); ovarian cancer Received: February 01, 2018 Accepted: April 16, 2018 Published: June 19, 2018 ABSTRACT NAC1 is a cancer-related transcription regulator protein that is overexpressed in various carcinomas, including ovarian, cervical, breast, and pancreatic carcinomas. NAC1 knock-down was previously shown to result in the apoptosis of ovarian cancer cell lines and to rescue their sensitivity to chemotherapy, suggesting that NAC1 may be a potential therapeutic target, but protein complex formation of intranuclear NAC1 in ovarian cancer cells remain poorly understood. In this study, analysis of ovarian cancer cell lysates by fast protein liquid chromatography on a sizing column showed that the NAC1 peak corresponded to an apparent molecular mass of 300–500 kDa, which is larger than the estimated molecular mass (58 kDa) of the protein. Liquid chromatography-tandem mass spectrometry analysis identified CARM1 as interacting with NAC1 in the protein complex. Furthermore, tissue microarray analysis revealed a significant correlation between CARM1 and NAC1 expression levels. Ovarian cancer patients expressing high levels of NAC1 and CARM1 exhibited poor prognosis after adjuvant chemotherapy. Collectively, our results demonstrate that high expression levels of NAC1 and its novel binding partner CARM1 may serve as an informative prognostic biomarker for predicting resistance to chemotherapy for ovarian cancer.