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Published on: May 3, 2021
Targeting USP9x/SOX2 axis contributes to the anti-osteosarcoma effect of neogambogic acid
Xiangyun Chen1, Xingming Zhang2, Haiyan Cai3
1Hongqiao International Institute of Medicine, Shanghai Tongren Hospital / Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of Transfusion Medicine, Shanghai Ninth Pevople's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Abstract:
SOX2 has been viewed as a critical oncoprotein in osteosarcoma. Emerging evidence show that inducing the degradation of transcription factors such as SOX2 is a promising strategy to make them druggable. Here, we show that neogambogic acid (NGA), an active ingredient in garcinia, significantly inhibited the proliferation of osteosarcoma cells with ubiquitin proteasome-mediated degradation of SOX2 in vitro and in vivo. We further identified USP9x as a bona fide deubiquitinase for SOX2 and NGA directly interacts with USP9x in cells. Moreover, knockdown of USP9x inhibited the proliferation and colony formation of osteosarcoma cells, which could be rescued by overexpression of SOX2. Consistent with this, knockdown of USP9x inhibited the proliferation of osteosarcoma cells in a xenograft mouse model. Collectively, we identify USP9x as the first deubiquitinating enzyme for controlling the stability of SOX2 and USP9x is a direct target for NGA. We propose that targeting the USP9x/SOX2 axis represents a novel strategy for the therapeutic of osteosarcoma and other SOX2 related cancers.
Insights
Neogambogic acid (NGA) degrades the oncoprotein SOX2, inhibiting osteosarcoma growth. This study identifies USP9x as a deubiquitinase for SOX2 and a target of NGA, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- SOX2 is a critical oncoprotein in osteosarcoma.
- Targeting transcription factor degradation is a promising therapeutic strategy.
Purpose of the Study:
- To investigate the effect of neogambogic acid (NGA) on osteosarcoma cells.
- To identify the mechanism by which NGA inhibits osteosarcoma proliferation.
- To explore the role of USP9x in SOX2 stability and osteosarcoma progression.
Main Methods:
- In vitro and in vivo studies of osteosarcoma cell proliferation.
- Ubiquitin-proteasome mediated degradation assays.
- Identification of deubiquitinating enzymes using biochemical assays.
- Gene knockdown and overexpression studies.
- Xenograft mouse models.
Main Results:
- NGA significantly inhibited osteosarcoma cell proliferation via SOX2 degradation.
- USP9x was identified as a deubiquitinase for SOX2.
- NGA directly interacts with USP9x.
- USP9x knockdown inhibited osteosarcoma cell proliferation, which was rescued by SOX2 overexpression.
Conclusions:
- USP9x is the first identified deubiquitinating enzyme controlling SOX2 stability.
- USP9x is a direct target of NGA.
- Targeting the USP9x/SOX2 axis is a novel therapeutic strategy for osteosarcoma and other SOX2-related cancers.
