Yi Sun (academic)

Yi Sun (孙毅) is a Chinese–American distinguished molecular biologist and oncologist, specialized in protein ubiquitylation and neddylation. He served as professor emeritus of Radiation Oncology at University of Michigan. He is the Qiushi Chair Professor at the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, China.

Sun has published more than 300 papers in peer-reviewed journals with an H-index of 77 and over 38,500 citations. He is a fellow of the American Association for the Advancement of Science (AAAS) since 2012.

Education

In 1982, Sun earned his M.D. degree at Jiangxi Medical College, Nanchang, China, and continued at Zhejiang University School of Medicine, Hangzhou, China, obtaining his M.S. degree in biochemistry in 1985.

He went to US in 1986 and obtained his PhD in Radiation biology from the University of Iowa, Iowa City, USA in 1989. Thereafter, Sun spent 5 years at the National Cancer Institute as a postdoc fellow, later as a senior staff fellow from 1990 to 1995.

Career

Following his tenure at the NCI, Sun spent 8 years in Parke-Davis/Pfizer as Research Fellow for cancer target identification and drug discovery in Ann Arbor, Michigan.

Sun then joined the faculty of University of Michigan, Ann Arbor, MI, USA in 2003, and was promoted to tenured full professor and Director of the Division of Radiation and Cancer Biology in 2008.

He retired from University of Michigan as a professor emeritus of Radiation Oncology in 2020.

Sun also served as the founding Dean at the Institute of Translational Medicine, Zhejiang University, China from 2014 to 2018.

Research

Sun has research expertise in cancer biology, radiation oncology, and translational medicine, specialized in protein ubiquitylation and neddylation, and their role in cancer.

SAG/RBX2 E3 ligase is a validated anti-cancer target

Sun cloned SAG (Sensitive to Apoptosis Gene), also known as RBX2, as an antioxidant protein, and a RING component of Cullin-RING ubiquitin ligases (CRLs), required for their activities; He and his team discovered that Sag is essential for mouse development, as well as for angiogenesis and apoptosis protection. The team validated SAG as a target for anti-cancer drug discovery by demonstrating its promoting role during tumorigenesis in the lung, prostate, and pancreas; and its overexpression in human cancer tissues with positive correlation to poor survival of cancer patients.

SAG-CRLs regulates many important biological processes via targeting degradation of key proteins

Sun and his team identified a number of key regulatory proteins as the substrates of CRLs that control a variety of important signal pathways and biological processes, particularly in growth and survival of cancer cells. These substrates include DEPTOR, Nf1, c-Jun, IκBα, Erbin, NOXA, XRCC4, SHOC2, SKP2, β-Catenin, MSX2, ASCT2, and DIRAS-2, as well as procaspase-3, HIF-1α, p27, MFN1, and EGR1. Targeted inhibition of CRLs causes accumulation of the tumor suppressors to inhibit cancer cell growth and cancer development.

Elucide neddylation function and discover neddylation inhibitors as novel anticancer agents

Sun and his team showed a cross-talk between two neddylation E2s, and neddylation E2/E3 regulated the functions of immune cells. The team also found that E1 inhibitor MLN4924 sensitizes pancreatic cancer cells to radiation; regulates stem cell proliferation and differentiation; and strikingly suppressed tumorigenesis in the lung and pancreas, triggered by mutant KrasG12D as a single agent. The study in the lung tumorigenesis triggered an intensive collaboration with Takeda Pharmaceutics, Inc., leading to an investigator-initiated Phase II clinical trials of MLN4924 (also known as pevonedistat) plus Docetaxel in patients with previously treated advanced non-small cell lung cancer. In drug discovery side, Sun and his team discovered small molecule inhibitors of neddylation E1, and neddylation E2 UBE2F as well as UBE2M-DCN interactions in collaboration with S. Wang's team in University of Michigan.

Selected publications

• Duan, H., Wang, Y., Aviram, M., Swaroop, M., Loo, J. A., Bian, J., Tian, Y., Mueller, T., Bisgaier, C. L., and Sun, Y. (1999) SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents. Mol Cell Biol 19, 3145–3155
• Swaroop, M., Wang, Y., Miller, P., Duan, H., Jatkoe, T., Madore, S., and Sun, Y. (2000) Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: Chip profiling implicates its role in cell cycle regulation. Oncogene 19, 2855–2866
• Tan, M., Zhao, Y., Kim, S. J., Liu, M., Jia, L., Saunders, T. L., Zhu, Y., and Sun, Y. (2011) SAG/RBX2/ROC2 E3 Ubiquitin Ligase Is Essential for Vascular and Neural Development by Targeting NF1 for Degradation. Dev Cell 21, 1062–1076
• Sun, Y., and Li, H. (2013) Functional characterization of SAG/RBX2/ROC2/RNF7, an antioxidant protein and an E3 ubiquitin ligase. Protein Cell 4, 103–116
• Zhao, Y., Xiong, X., and Sun, Y. (2020) Cullin-RING Ligase 5: Functional characterization and its role in human cancers. Semin Cancer Biol 67, 61–79
• Li, H., Tan, M., Jia, L., Wei, D., Zhao, Y., Chen, G., Xu, J., Zhao, L., Thomas, D., Beer, D. G., and Sun, Y. (2014) Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis. J Clin Invest 124, 835-846
• Zhao, Y., Xiong, X., and Sun, Y. (2011) DEPTOR, an mTOR Inhibitor, Is a Physiological Substrate of SCFβTrCP E3 Ubiquitin Ligase and Regulates Survival and Autophagy. Mol Cell 44, 304-316
• Zhang, S., You, X., Zheng, Y., Shen, Y., Xiong, X., and Sun, Y. (2023) The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells. J Clin Invest 133