- Chen, Ye;
- Xu, Liang;
- Mayakonda, Anand;
- Huang, Mo-Li;
- Kanojia, Deepika;
- Tan, Tuan Zea;
- Dakle, Pushkar;
- Lin, Ruby Yu-Tong;
- Ke, Xin-Yu;
- Said, Jonathan W;
- Chen, Jianxiang;
- Gery, Sigal;
- Ding, Ling-Wen;
- Jiang, Yan-Yi;
- Pang, Angela;
- Puhaindran, Mark Edward;
- Goh, Boon Cher;
- Koeffler, H Phillip
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.