張雋曦 Chun Hei Antonio Cheung

發現BIRC5 存活素的新功能 增進對癌症的了解

I have a long interest in studying the functions of a family of molecules called inhibitors-of-apoptosis proteins (IAPs), with focus on a family member called BIRC5/Survivin in cells. Since its discovery two decades ago, people mainly believe that BIRC5 has two cellular functions: inhibits apoptosis and promotes mitosis. Recently, my research group discovered that BIRC5 also negatively-regulates autophagy in mammalian cells. We are among the first to found that the BIRC5 expression suppressant, YM155 (a compound reached phase II clinical trial), induces cancer cell death in an autophagy-dependent manner (Cheng et al., British Journal of Pharmacology 2015). At the molecular level, BIRC5 physically binds to ATG12-ATG5 conjugate, subsequently inhibiting the formation of the ATG12-ATG5-ATG16L complex, resulting in the suppression of the formation of autophagosome (Lin et al., Autophagy 2020).

My research group also discovered a surprising molecular phenomenon that BIRC5 promotes genomic stability through suppressing autophagy (Cheng et al., Pharmacological Research 2021), as opposing to the current consensus in the field of autophagy that autophagy activation promotes DNA repair and genomic stability. Despite BIRC5 is not expressed (or expressed at an undetectable low level) in the differentiated normal tissues, expression of BIRC5 is known to be physiologically important for the development of the brain and heart during embryogenesis. Pathologically, overexpression of BIRC5 is long known to promote tumorigenesis, tumor drug resistance and tumor metastasis.

Autophagy is an important physiological process that needs high level of regulation and dysregulation of autophagy promotes the development of various diseases like cancers and Alzheimer's disease. Better understanding on the regulation and functions of BIRC5 and autophagy, especially at different cellular and molecular conditions, will for sure to help us to have a better understanding on the development of difference diseases and to develop better therapeutic strategies for treating these diseases.