TY - JOUR
T1 - Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells
AU - Zhou, Qiyin
AU - Lin, Wenyu
AU - Wang, Chaoqun
AU - Sun, Fei
AU - Ju, Siwei
AU - Chen, Qian
AU - Wang, Yi
AU - Chen, Yongxia
AU - Li, Haomin
AU - Wang, Linbo
AU - Hu, Zeping
AU - Jin, Hongchuan
AU - Wang, Xian
AU - Sun, Yi
N1 - Funding Information:
This work is supported in part by the National Key R&D Program of China (2021YFA1101000 and 2016YFA0501800 to YS), Chinese NSFC grant (31701167 to QZ), and Zhejiang Provincial Natural Science Foundation of China (LD22H300003 to YS).
Funding Information:
We would like to thank Drs. Ping Wang, Xinbo Wang, and Desheng Du for providing various expressing plasmids. We would also like to thank the staff members from the Core facilities and the Morphological Platform at Zhejiang University School of Medicine for their assistance in data collection and technical support. This work is supported in part by the National Key R&D Program of China (2021YFA1101000 and 2016YFA0501800 to YS), Chinese NSFC grant (31701167 to QZ), and Zhejiang Provincial Natural Science Foundation of China (LD22H300003 to YS).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Abnormal neddylation activation is frequently observed in human cancers and neddylation inhibition has been proposed as a therapy for cancer. Here, we report that MLN4924, a small-molecule inhibitor of neddylation activating enzyme, increases glutamine uptake in breast cancer cells by causing accumulation of glutamine transporter ASCT2/SLC1A5, via inactivation of CRL3-SPOP E3 ligase. We show the E3 ligase SPOP promotes ASCT2 ubiquitylation, whereas SPOP itself is auto-ubiquitylated upon glutamine deprivation. Thus, SPOP and ASCT2 inversely regulate glutamine uptake and metabolism. SPOP knockdown increases ASCT2 levels to promote growth which is rescued by ASCT2 knockdown. Adding ASCT2 inhibitor V-9302 enhances MLN4924 suppression of tumor growth. In human breast cancer specimens, SPOP and ASCT2 levels are inversely correlated, whereas lower SPOP with higher ASCT2 predicts a worse patient survival. Collectively, our study links neddylation to glutamine metabolism via the SPOP-ASCT2 axis and provides a rational drug combination for enhanced cancer therapy.
AB - Abnormal neddylation activation is frequently observed in human cancers and neddylation inhibition has been proposed as a therapy for cancer. Here, we report that MLN4924, a small-molecule inhibitor of neddylation activating enzyme, increases glutamine uptake in breast cancer cells by causing accumulation of glutamine transporter ASCT2/SLC1A5, via inactivation of CRL3-SPOP E3 ligase. We show the E3 ligase SPOP promotes ASCT2 ubiquitylation, whereas SPOP itself is auto-ubiquitylated upon glutamine deprivation. Thus, SPOP and ASCT2 inversely regulate glutamine uptake and metabolism. SPOP knockdown increases ASCT2 levels to promote growth which is rescued by ASCT2 knockdown. Adding ASCT2 inhibitor V-9302 enhances MLN4924 suppression of tumor growth. In human breast cancer specimens, SPOP and ASCT2 levels are inversely correlated, whereas lower SPOP with higher ASCT2 predicts a worse patient survival. Collectively, our study links neddylation to glutamine metabolism via the SPOP-ASCT2 axis and provides a rational drug combination for enhanced cancer therapy.
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U2 - 10.1038/s41467-022-30559-2
DO - 10.1038/s41467-022-30559-2
M3 - Article
C2 - 35641493
AN - SCOPUS:85131006439
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3034
ER -