Abstract
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.
Highlights
Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation
We demonstrate that (1) bromodomain and extraterminal (BET) proteins are vital to maintain the differentiated LPS (DDLPS)-specific core transcriptional regulatory circuitry consisting of SE-associated Transcription factors (TFs) FOSL2, MYC, and RUNX1; and (2)
To evaluate the active epigenetic states associated with LPS malignancy, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) of histone mark H3K27ac in both LPS cell lines and primary tumors
Summary
Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. Liposarcomas (LPSs) are a group of mesenchymal malignancies showing adipocytic differentiation and are the prevailing types of soft tissue sarcomas in adults[2]. LPSs are heterogeneous diseases with four major subtypes: well-differentiated LPS (WDLPS), de-differentiated LPS (DDLPS), myxoid LPS (MLPS), and pleomorphic LPS (PLPS). The latter three comprise the majority of high-grade cases. Tremendous efforts have been made to determine genomic and epigenetic defects that block terminal differentiation of high-grade LPS, whereas the feed-forward transcriptional regulatory mechanism that reinforces and stabilizes the malignant characteristics remains unexplored
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