Stabilization of Cyclin-Dependent Kinase 4 by Methionyl-tRNA Synthetase in p16INK4a-Negative Cancer

Nam Hoon Kwon; Jin Young Lee; Ye-Lim Ryu; Chanhee Kim; Jiwon Kong; Seongeun Oh; Beom Sik Kang; Hye Won Ahn; Sung Gwe Ahn; Joon Jeong; Hoi Kyoung Kim; Jong Hyun Kim; Dae Young Han; Min Chul Park; Doyeun Kim; Ryuichi Takase; Isao Masuda; Ya-Ming Hou; Sung Ill Jang; Yoon Soo Chang; Dong Ki Lee; Youngeun Kim; Ming-Wei Wang; Basappa; Sunghoon Kim

doi:10.1021/acsptsci.8b00001

Stabilization of Cyclin-Dependent Kinase 4 by Methionyl-tRNA Synthetase in p16^INK4a-Negative Cancer

ACS Pharmacol Transl Sci. 2018 Apr 24;1(1):21-31. doi: 10.1021/acsptsci.8b00001. eCollection 2018 Sep 14.

Authors

Nam Hoon Kwon^{1

2}, Jin Young Lee¹, Ye-Lim Ryu¹, Chanhee Kim¹, Jiwon Kong¹, Seongeun Oh¹, Beom Sik Kang³, Hye Won Ahn¹, Sung Gwe Ahn⁴, Joon Jeong⁴, Hoi Kyoung Kim¹, Jong Hyun Kim¹, Dae Young Han¹, Min Chul Park¹, Doyeun Kim¹, Ryuichi Takase⁵, Isao Masuda⁵, Ya-Ming Hou⁵, Sung Ill Jang⁶, Yoon Soo Chang⁶, Dong Ki Lee⁶, Youngeun Kim¹, Ming-Wei Wang⁷, Basappa⁸, Sunghoon Kim^{1

2}

Affiliations

¹ Medicinal Bioconvergence Research Center, Seoul National University, Suwon, 16229, Korea.
² Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Korea.
³ School of Life Science and Biotechnology, Kyungpook National University, Daegu, 41566, Korea.
⁴ Breast Cancer Center, Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea.
⁵ Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States.
⁶ Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea.
⁷ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁸ Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore, 560 001, India.

Abstract

Although abnormal increases in the level or activity of cyclin-dependent kinase 4 (CDK4) occur frequently in cancer, the underlying mechanism is not fully understood. Here, we show that methionyl-tRNA synthetase (MRS) specifically stabilizes CDK4 by enhancing the formation of the complex between CDK4 and a chaperone protein. Knockdown of MRS reduced the CDK4 level, resulting in G0/G1 cell cycle arrest. The effects of MRS on CDK4 stability were more prominent in the tumor suppressor p16^INK4a-negative cancer cells because of the competitive relationship of the two proteins for binding to CDK4. Suppression of MRS reduced cell transformation and the tumorigenic ability of a p16^INK4a-negative breast cancer cell line in vivo. Further, the MRS levels showed a positive correlation with those of CDK4 and the downstream signals at high frequency in p16^INK4a-negative human breast cancer tissues. This work revealed an unexpected functional connection between the two enzymes involving protein synthesis and the cell cycle.