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

doi:10.1016/j.ygeno.2021.02.017

	Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells
	Liu, Yuwei 1,2; Xue, Mengzhu 1; Cao, Danyan 2; Qin, Lihuai 3; Wang, Ying 2; Miao, Zehong 2; Wang, Peng 4; Hu, Xin 5; Shen, Jingkang 2; Xiong, Bing 2
刊名	GENOMICS
	2021-05-01
卷号	113 期号:3 页码:1057-1069
关键词	Multi-omics BET inhibitor responses WNT pathway Liver cancer Precise therapy
ISSN号	0888-7543
DOI	10.1016/j.ygeno.2021.02.017
通讯作者	Xue, Mengzhu(xuemz@sari.ac.cn) ; Wang, Peng(wangpeng@picb.ac.cn) ; Hu, Xin(xinhu@fudan.edu.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要	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.
资助项目	Science and Technology Commission of Shanghai Municipality Project[16ZR1449000] ; National Natural Science Foundation of China (NSFC)[31701154] ; National Natural Science Foundation of China (NSFC)[81330076] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-011-018]
WOS关键词	WNT/BETA-CATENIN PATHWAY ; HEPATOCELLULAR-CARCINOMA ; BREAST-CANCER ; GROWTH ; ACTIVATION ; SCALE ; NOTUM ; DHRS2 ; DKK1
WOS研究方向	Biotechnology & Applied Microbiology ; Genetics & Heredity
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000661250200006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297114]
专题	中国科学院上海药物研究所
通讯作者	Xue, Mengzhu; Wang, Peng; Hu, Xin; Xiong, Bing
作者单位	1.Chinese Acad Sci, Shanghai Adv Res Inst, SARI Ctr Stem Cell & Nanomed, Shanghai 201210, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Pharmacol Sci, Ctr Chem Biol & Drug Discovery, New York, NY 10029 USA 4.Chinese Acad Sci, Shanghai Inst Biol Sci, CAS MPG Partner Inst Computat Biol, Biomed Big Data Ctr,Key Lab Computat Biol, Shanghai 200031, Peoples R China 5.Fudan Univ, Shanghai Canc Ctr, Shanghai 200032, Peoples R China
推荐引用方式 GB/T 7714	Liu, Yuwei,Xue, Mengzhu,Cao, Danyan,et al. Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells[J]. GENOMICS,2021,113(3):1057-1069.
APA	Liu, Yuwei.,Xue, Mengzhu.,Cao, Danyan.,Qin, Lihuai.,Wang, Ying.,...&Xiong, Bing.(2021).Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells.GENOMICS,113(3),1057-1069.
MLA	Liu, Yuwei,et al."Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells".GENOMICS 113.3(2021):1057-1069.