Small-molecule induction of phospho-eIF4E sumoylation and degradation via targeting its phosphorylated serine 209 residue

// Ying Gu 1, 2, 3, * , Hong Zhou 1, 2, * , Yichao Gan 1, 2, * , Jiawei Zhang 2, 3, * , Jianghua Chen 1, 2 , Xiaoxian Gan 3, 4 , Hongzhi Li 5 , Weiwei Zheng 1, 2 , Zhipeng Meng 3 , Xiaoxiao Ma 3 , Xichun Wang 3 , Xiaohua Xu 1 , Ganyu Xu 3 , Xiaoya Lu 1, 2 , Yun Liang 1 , Xuzhao Zhang 1 , Xinliang Lu 2 , Wendong Huang 3 , Rongzhen Xu 1, 2 1 Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China 2 Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China 3 Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA 4 Zhejiang Academy of Medical Sciences, Hangzhou, 310012, China 5 Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA * These authors have contributed equally to this work Correspondence to: Rongzhen Xu, e-mail: zrxyk10@zju.edu.cn Wendong Huang, e-mail: whuang@coh.org Keywords: phospho-eIF4E, homoharritonine, small molecular inhibitor, proteasome-dependent degradation, acute myeloid leukemia Received: February 04, 2015      Accepted: March 14, 2015      Published: April 10, 2015 ABSTRACT As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo . HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.