TY - JOUR
T1 - USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
AU - Qin, Kewei
AU - Yu, Shuhan
AU - Liu, Yang
AU - Guo, Rongtian
AU - Guo, Shiya
AU - Fei, Junjie
AU - Wang, Yuemeng
AU - Jia, Kaiyuan
AU - Xu, Zhiqiang
AU - Chen, Hu
AU - Li, Fengtian
AU - Niu, Mengmeng
AU - Dai, Mu Shui
AU - Dai, Lunzhi
AU - Cao, Yang
AU - Zhang, Yujun
AU - Xiao, Zhi Xiong Jim
AU - Yi, Yong
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - Tumor growth requires elevated ribosome biogenesis. Targeting ribosomes is an important strategy for cancer therapy. The ribosome inhibitor, homoharringtonine (HHT), is used for the clinical treatment of leukemia, yet it is ineffective for the treatment of solid tumors, the reasons for which remain unclear. Here we show that Snail1, a key factor in the regulation of epithelial-to-mesenchymal transition, plays a pivotal role in cellular surveillance response upon ribotoxic stress. Mechanistically, ribotoxic stress activates the JNK-USP36 signaling to stabilize Snail1 in the nucleolus, which facilitates ribosome biogenesis and tumor cell survival. Furthermore, we show that HHT activates the JNK-USP36-Snail1 axis in solid tumor cells, but not in leukemia cells, resulting in solid tumor cell resistance to HHT. Importantly, a combination of HHT with the inhibition of the JNK-USP36-Snail1 axis synergistically inhibits solid tumor growth. Together, this study provides a rationale for targeting the JNK-USP36-Snail1 axis in ribosome inhibition-based solid tumor therapy.
AB - Tumor growth requires elevated ribosome biogenesis. Targeting ribosomes is an important strategy for cancer therapy. The ribosome inhibitor, homoharringtonine (HHT), is used for the clinical treatment of leukemia, yet it is ineffective for the treatment of solid tumors, the reasons for which remain unclear. Here we show that Snail1, a key factor in the regulation of epithelial-to-mesenchymal transition, plays a pivotal role in cellular surveillance response upon ribotoxic stress. Mechanistically, ribotoxic stress activates the JNK-USP36 signaling to stabilize Snail1 in the nucleolus, which facilitates ribosome biogenesis and tumor cell survival. Furthermore, we show that HHT activates the JNK-USP36-Snail1 axis in solid tumor cells, but not in leukemia cells, resulting in solid tumor cell resistance to HHT. Importantly, a combination of HHT with the inhibition of the JNK-USP36-Snail1 axis synergistically inhibits solid tumor growth. Together, this study provides a rationale for targeting the JNK-USP36-Snail1 axis in ribosome inhibition-based solid tumor therapy.
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UR - http://www.scopus.com/inward/citedby.url?scp=85174232750&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-42257-8
DO - 10.1038/s41467-023-42257-8
M3 - Article
C2 - 37833415
AN - SCOPUS:85174232750
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6473
ER -