Frontiers in Oncology (Jan 2020)
Targeting BET Proteins With a PROTAC Molecule Elicits Potent Anticancer Activity in HCC Cells
- Huapeng Zhang,
- Huapeng Zhang,
- Huapeng Zhang,
- Huapeng Zhang,
- Gongquan Li,
- Gongquan Li,
- Gongquan Li,
- Gongquan Li,
- Yi Zhang,
- Yi Zhang,
- Jihua Shi,
- Jihua Shi,
- Jihua Shi,
- Jihua Shi,
- Bing Yan,
- Bing Yan,
- Bing Yan,
- Bing Yan,
- Hongwei Tang,
- Hongwei Tang,
- Hongwei Tang,
- Hongwei Tang,
- Sanyang Chen,
- Sanyang Chen,
- Sanyang Chen,
- Sanyang Chen,
- Jiakai Zhang,
- Jiakai Zhang,
- Jiakai Zhang,
- Jiakai Zhang,
- Peihao Wen,
- Peihao Wen,
- Peihao Wen,
- Peihao Wen,
- Zhihui Wang,
- Zhihui Wang,
- Zhihui Wang,
- Zhihui Wang,
- Chun Pang,
- Chun Pang,
- Chun Pang,
- Chun Pang,
- Jie Li,
- Jie Li,
- Jie Li,
- Jie Li,
- Wenzhi Guo,
- Wenzhi Guo,
- Wenzhi Guo,
- Wenzhi Guo,
- Shuijun Zhang,
- Shuijun Zhang,
- Shuijun Zhang,
- Shuijun Zhang
Affiliations
- Huapeng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Huapeng Zhang
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Huapeng Zhang
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Huapeng Zhang
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Gongquan Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gongquan Li
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gongquan Li
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Gongquan Li
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Yi Zhang
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Yi Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jihua Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jihua Shi
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jihua Shi
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Jihua Shi
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Bing Yan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Bing Yan
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Bing Yan
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Bing Yan
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Hongwei Tang
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Hongwei Tang
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Hongwei Tang
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Sanyang Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Sanyang Chen
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Sanyang Chen
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Sanyang Chen
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Jiakai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jiakai Zhang
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jiakai Zhang
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Jiakai Zhang
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Peihao Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Peihao Wen
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Peihao Wen
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Peihao Wen
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Zhihui Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhihui Wang
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhihui Wang
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Zhihui Wang
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Chun Pang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Chun Pang
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Chun Pang
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Chun Pang
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Jie Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jie Li
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jie Li
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Jie Li
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Wenzhi Guo
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Wenzhi Guo
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Wenzhi Guo
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Shuijun Zhang
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Shuijun Zhang
- Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China
- Shuijun Zhang
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- DOI
- https://doi.org/10.3389/fonc.2019.01471
- Journal volume & issue
-
Vol. 9
Abstract
Background and Aim: Bromodomain and extraterminal domain (BET) family proteins are epigenetic regulators involved in human malignances. Targeting BET proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer therapeutics. BET proteins have been found to be overexpressed in HCC cells and tumor tissues. However, the biological activity of BET-PROTACs in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated anti-HCC activity of BETd-260, a BET-PROTAC molecule using in vitro and in vivo models.Methods: BETd-260-mediated anti-HCC activity was investigated by cell viability, apoptosis assays. Efficacy was examined with a cell lines-derived HCC xenograft model in mice. Anticancer mechanism was investigated by RT-PCR, western blotting and immunohistochemical staining.Results: BETd-260 potently suppressed cell viability and robustly induced apoptosis in HCC cells. BETd-260 reciprocally modulated the expression of several apoptotic genes in HCC cells, i.e., suppressing the expression of anti-apoptotic Mcl-1, Bcl-2, c-Myc, and X-linked inhibitor of apoptosis (XIAP), whereas increasing the expression of pro-apoptotic Bad. BETd-260 treatment led to disruption of mitochondrial membrane integrity, and triggered apoptosis via intrinsic signaling in HCC cells. BETd-260 triggered apoptosis in HCC xenograft tissue and profoundly inhibited the growth of HCC xenograft tumors in mice.Conclusion: Our data suggest that pharmacological targeting of BET for degradation may be a novel therapeutic strategy for the treatment of HCC.
Keywords
