Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma.
Ye ChenLiang XuAnand MayakondaMo-Li HuangDeepika KanojiaTuan-Zea TanPushkar DakleRuby Yu-Tong LinXin-Yu KeJonathan W SaidJianxiang ChenSigal GeryLing-Wen DingYan-Yi JiangAngela PangMark Edward PuhaindranBoon Cher GohH Phillip KoefflerPublished in: Nature communications (2019)
Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.
Keyphrases
- transcription factor
- inflammatory response
- anti inflammatory
- gene expression
- binding protein
- induced apoptosis
- genome wide
- protein protein
- cell cycle arrest
- stem cells
- public health
- genome wide identification
- amino acid
- squamous cell carcinoma
- heat shock
- emergency department
- signaling pathway
- dna methylation
- climate change
- bone marrow
- endoplasmic reticulum stress
- single cell
- induced pluripotent stem cells
- radiation induced
- heat stress