TY - JOUR
T1 - The deubiquitinating enzyme STAMBP is a newly discovered driver of triple-negative breast cancer progression that maintains RAI14 protein stability
AU - Yang, Qianqian
AU - Yan, Ding
AU - Zou, Chaoying
AU - Xue, Qian
AU - Lin, Shuhui
AU - Huang, Qingtian
AU - Li, Xiaofen
AU - Tang, Daolin
AU - Chen, Xin
AU - Liu, Jinbao
N1 - Funding Information:
The study was supported by the Basic and Applied Basic Research Project of the Guangzhou Basic Research Program (202201011411), NSFC (Nos. 81802405, 81602427, 81772492, 82272660, and 81900365), the National Funds for Developing Local Colleges and Universities (B16056001), Natural Science Foundation Research Team of Guangdong Province (2018B030312001, 2017A030310151, and 2016A030310281), the Science and Technology Program of Guangzhou (201604020001), the Innovative Academic Team of the Guangzhou Education System (1201610014), and the Research Team of Department of Education of Guangdong Province (2017KCXTD027).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/11
Y1 - 2022/11
N2 - Triple-negative breast cancer (TNBC) is a heterogeneous malignancy in women. It is associated with poor prognosis, aggressive malignant behavior, and limited treatment options. In the ubiquitin‒proteasome system (UPS), deubiquitinases (DUBs) are potential therapeutic targets for various tumors. In this study, by performing unbiased siRNA screening, we identified STAMBP, a JAMM metalloprotease in the DUB family, as a driver of human TNBC tumor growth. Functionally, the knockdown of STAMBP inhibited the proliferation, migration, and invasion of multiple TNBC cell lines. Immunoprecipitation–mass spectrometry combined with functional and morphological analysis verified the interaction between STAMBP and the actin-binding protein RAI14. Mechanistically, STAMBP stabilized the RAI14 protein by suppressing the K48-linked ubiquitination of RAI14 and thus prevented its proteasomal degradation. Therefore, knocking down STAMBP resulted in the reduction in RAI14 protein levels and suppression of tumor growth in vitro and in vivo. Importantly, high levels of STAMBP were correlated with poor prognosis in TNBC patients. In summary, we reveal a previously unrecognized DUB pathway that promotes TNBC progression and provides a rationale for potential therapeutic interventions for the treatment of TNBC.
AB - Triple-negative breast cancer (TNBC) is a heterogeneous malignancy in women. It is associated with poor prognosis, aggressive malignant behavior, and limited treatment options. In the ubiquitin‒proteasome system (UPS), deubiquitinases (DUBs) are potential therapeutic targets for various tumors. In this study, by performing unbiased siRNA screening, we identified STAMBP, a JAMM metalloprotease in the DUB family, as a driver of human TNBC tumor growth. Functionally, the knockdown of STAMBP inhibited the proliferation, migration, and invasion of multiple TNBC cell lines. Immunoprecipitation–mass spectrometry combined with functional and morphological analysis verified the interaction between STAMBP and the actin-binding protein RAI14. Mechanistically, STAMBP stabilized the RAI14 protein by suppressing the K48-linked ubiquitination of RAI14 and thus prevented its proteasomal degradation. Therefore, knocking down STAMBP resulted in the reduction in RAI14 protein levels and suppression of tumor growth in vitro and in vivo. Importantly, high levels of STAMBP were correlated with poor prognosis in TNBC patients. In summary, we reveal a previously unrecognized DUB pathway that promotes TNBC progression and provides a rationale for potential therapeutic interventions for the treatment of TNBC.
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U2 - 10.1038/s12276-022-00890-1
DO - 10.1038/s12276-022-00890-1
M3 - Article
C2 - 36434041
AN - SCOPUS:85142615089
SN - 1226-3613
VL - 54
SP - 2047
EP - 2059
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
IS - 11
ER -