Roles of USP1 in Ewing sarcoma
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https://doi.org/10.18632/genesandcancer.235
Panneerselvam Jayabal1, Xiuye Ma1 and Yuzuru Shiio1,2,3
1 Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
2 Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA
3 Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Correspondence to:
Yuzuru Shiio, email:[email protected]
Keywords: chemotherapy; Ewing sarcoma; growth; USP1
Received: August 28, 2023 Accepted: December 19, 2023 Published: February 05, 2024
Abstract
Ewing sarcoma is a cancer of bone and soft tissue in children and young adults that is driven by the EWS-ETS fusion transcription factor, most commonly EWS-FLI1. We previously reported that Ewing sarcoma harbors two populations of cells, the CD133high population displaying higher growth rate and the CD133low population displaying chemotherapy resistance. We now find that the ubiquitin-specific protease 1 (USP1) is a transcriptional target of the EWS-FLI1 fusion oncoprotein, expressed at high and low levels in the CD133high and the CD133low populations, respectively, and determines chemo-sensitivity. We also find that USP1 inhibits cdc42, increases EWS-FLI1 transcriptional output, and simulates Ewing sarcoma growth. We show that chemo-sensitization by USP1 is independent of cdc42. A pharmacological inhibitor of USP1 was able to activate cdc42 and inhibit Ewing sarcoma growth. These results uncover critical roles for USP1 in Ewing sarcoma, which regulates growth and chemo-sensitivity via distinct mechanisms.