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Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells
- Source :
- Genomics. 113:1057-1069
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- 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-6-171 resistant cells. Specially, combinations of Hjp-6-171 and a GSK3β 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 β-catenin regulated genes is contrary in sensitive cells to that in resistant cells. We propose WNT signaling molecules such as β-catenin and ETV4 to be candidate biomarkers to indicate BET inhibitor responses in liver cancer patients.
- Subjects :
- 0106 biological sciences
Drug resistance
Biology
01 natural sciences
BET inhibitor
03 medical and health sciences
In vivo
Cell Line, Tumor
Genetics
medicine
Humans
Carbonyl Reductase (NADPH)
Wnt Signaling Pathway
beta Catenin
Cell Proliferation
030304 developmental biology
0303 health sciences
Liver Neoplasms
Wnt signaling pathway
medicine.disease
In vitro
Notum
Bromodomain
Gene Expression Regulation, Neoplastic
Cancer research
Liver cancer
010606 plant biology & botany
Subjects
Details
- ISSN :
- 08887543
- Volume :
- 113
- Database :
- OpenAIRE
- Journal :
- Genomics
- Accession number :
- edsair.doi.dedup.....c3a6e0ed1fd16c9cd8abe650124e5d1c