Pharmacological Inhibition of Core Regulatory Circuitry Liquid–liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma

Bing Lu, Changye Zou, Meiling Yang, Yangyang He, Jincan He, Chuanxia Zhang, Siyun Chen, Jiaming Yu, Kilia Yun Liu, Qi Cao, Wei Zhao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Liquid–liquid phase-separated (LLPS) transcriptional factor assemblies at super-enhancers (SEs) provide a conceptual framework for underlying transcriptional control in mammal cells. However, the mechanistic understanding of LLPS in aberrant transcription driven by dysregulation of SEs in human malignancies is still elusive. By integrating SE profiling and core regulatory circuitry (CRC) calling algorithm, the CRC of metastatic and chemo-resistant osteosarcoma is delineated. CRC components, HOXB8 and FOSL1, produce dense and dynamic phase-separated droplets in vitro and liquid-like puncta in cell nuclei. Disruption of CRC phase separation decreases the chromatin accessibility in SE regions and inhibits the release of RNA polymerase II from the promoter of SE-driven genes. Importantly, absence of CRC key component causes a reduction in osteosarcoma tumor growth and metastasis. Moreover, it is shown that CRC condensates can be specifically attenuated by the H3K27 demethylase inhibitor, GSK-J4. Pharmacological inhibition of the CRC phase separation results in metastasis suppression and re-sensitivity to chemotherapy drugs in patient-derived xenograft model. Taken together, this study reveals a previously unknown mechanism that CRC factors formed LLPS condensates, and provides a phase separation-based pharmacological strategy to target undruggable CRC components for the treatment of metastatic and chemo-resistant osteosarcoma.

Original languageEnglish (US)
Article number2101895
JournalAdvanced Science
Volume8
Issue number20
DOIs
StatePublished - Oct 20 2021

Keywords

  • HOXB8
  • core regulatory circuitry
  • liquid–liquid phase separation
  • osteosarcoma
  • super-enhancer

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Engineering(all)
  • Physics and Astronomy(all)

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