Regulation of EZH2 protein stability: new mechanisms, roles in tumorigenesis, and roads to the clinic
Yunyun Guo,
Rui Cheng,
Yuqing Wang,
Maria E. Gonzalez,
Hongshan Zhang,
Yang Liu,
Celina G. Kleer,
Lixiang Xue
Affiliations
Yunyun Guo
Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
Rui Cheng
Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
Yuqing Wang
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
Maria E. Gonzalez
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
Hongshan Zhang
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
Yang Liu
Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China; Corresponding author. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, No. 30, Xueyuan Road, 100191, Beijing, China.
Celina G. Kleer
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Corresponding author.
Lixiang Xue
Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China; Corresponding author. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, No. 30, Xueyuan Road, 100191, Beijing, China.
Summary: The importance of EZH2 as a key methyltransferase has been well documented theoretically. Practically, the first EZH2 inhibitor Tazemetostat (EPZ6438), was approved by FDA in 2020 and is used in clinic. However, for most solid tumors it is not as effective as desired and the scope of clinical indications is limited, suggesting that targeting its enzymatic activity may not be sufficient. Recent technologies focusing on the degradation of EZH2 protein have drawn attention due to their potential robust effects. This review focuses on the molecular mechanisms that regulate EZH2 protein stability via post-translational modifications (PTMs), mainly including ubiquitination, phosphorylation, and acetylation. In addition, we discuss recent advancements of multiple proteolysis targeting chimeras (PROTACs) strategies and the latest degraders that can downregulate EZH2 protein. We aim to highlight future directions to expand the application of novel EZH2 inhibitors by targeting both EZH2 enzymatic activity and protein stability.
