Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas

Yanli Cheng, Zhongtian Shen, Yaqi Gao, Feilong Chen, Huisha Xu, Qinling Mo, Xinlei Chu, Chang-liang Peng, Takese T. McKenzie, Bridgitte E. Palacios, Jian Hu, Hao Zhou () and Jiafu Long ()
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Yanli Cheng: Nankai University
Zhongtian Shen: Nankai University
Yaqi Gao: Nankai University
Feilong Chen: Nankai University
Huisha Xu: Nankai University
Qinling Mo: Nankai University
Xinlei Chu: Tianjin Medical University Cancer Institute and Hospital
Chang-liang Peng: Shandong University
Takese T. McKenzie: The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences
Bridgitte E. Palacios: The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences
Jian Hu: The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences
Hao Zhou: Nankai University
Jiafu Long: Nankai University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Oncoprotein SS18-SSX is a hallmark of synovial sarcomas. However, as a part of the SS18-SSX fusion protein, SS18’s function remains unclear. Here, we depict the structures of both human SS18/BRG1 and yeast SNF11/SNF2 subcomplexes. Both subcomplexes assemble into heterodimers that share a similar conformation, suggesting that SNF11 might be a homologue of SS18 in chromatin remodeling complexes. Importantly, our study shows that the self-association of the intrinsically disordered region, QPGY domain, leads to liquid-liquid phase separation (LLPS) of SS18 or SS18-SSX and the subsequent recruitment of BRG1 into phase-separated condensates. Moreover, our results show that the tyrosine residues in the QPGY domain play a decisive role in the LLPS of SS18 or SS18-SSX. Perturbations of either SS18-SSX LLPS or SS18-SSX’s binding to BRG1 impair NIH3T3 cell transformation by SS18-SSX. Our data demonstrate that both LLPS and assembling into chromatin remodelers contribute to the oncogenic activity of SS18-SSX in synovial sarcomas.

Date: 2022
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DOI: 10.1038/s41467-022-30447-9

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