Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells----上海高等研究院

中文

Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells

论文题目: Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells
作者: Liu, Yuwei; Xue, Mengzhu; Cao, Danyan; Qin, Lihuai; Wang, Ying; Miao, Zehong; Wang, Peng; Hu, Xin; Shen, Jingkang; Xiong, Bing
刊名: Genomics
出版年: 2021 卷: 113 期: 3 页: 1057-1069
关键词:
WNT/BETA-CATENIN PATHWAY; HEPATOCELLULAR-CARCINOMA; BREAST-CANCER; GROWTH; ACTIVATION; SCALE; NOTUM; DHRS2; DKK1
摘要:
The Bromodomain and Extra-terminal domain (BET) proteins are promising targets in treating cancers. Although BET inhibitors have been in clinical trials, they are limited by lacking of suitable biomarkers to indicate drug responses in different cancers. Here we identify DHRS2, ETV4 and NOTUM as potential biomarkers to indicate drug resistance in liver cancer cells of a recently discovered BET inhibitor, Hjp-6-171. Furthermore, we confirm that reactivation of WNT pathway, the target of NOTUM, contributes to the drug sensitivity restoration in Hjp-6171 resistant cells. Specially, combinations of Hjp-6-171 and a GSK38 inhibitor CHIR-98014 show remarkable therapeutic effects in vitro and in vivo. Integrating RNA-seq and ChIP-seq data, we reveal the expression signature of 8-catenin regulated genes is contrary in sensitive cells to that in resistant cells. We propose WNT signaling molecules such as 8-catenin and ETV4 to be candidate biomarkers to indicate BET inhibitor responses in liver cancer patients.