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- Title
USP29 enhances chemotherapy-induced stemness in non-small cell lung cancer via stabilizing Snail1 in response to oxidative stress.
- Authors
Wu, Yueguang; Zhang, Yingqiu; Wang, Duchuang; Zhang, Yang; Zhang, Jinrui; Zhang, Yayun; Xu, Lu; Wang, Taishu; Wang, Shanshan; Zhang, Qingqing; Liu, Fang; Zaky, Mohamed Y.; Li, Qiong; Sun, Qianhui; Guo, Dong; Liu, Shuyan; Zou, Lijuan; Yang, Qingkai; Liu, Han
- Abstract
Chemotherapy remains an essential part of diverse treatment regimens against human malignancies. However, recent progressions have revealed a paradoxical role of chemotherapies to induce the cancer stem cell-like features that facilitate chemoresistance and tumor dissemination, with the underlying mechanisms underinvestigated. The zinc-finger transcription factor Snail1 is a central regulator during the epithelial-mesenchymal transition process and is closely implicated in cancer progression. Snail1 expression is strictly regulated at multiple layers, with its stability governed by post-translational ubiquitylation that is counterbalanced by the activities of diverse E3 ligases and deubiquitylases. Here we identify the deubiquitylase USP29 as a novel stabilizer of Snail1, which potently restricts its ubiquitylation in a catalytic activity-dependent manner. Bioinformatic analysis reveals a reverse correlation between USP29 expression and prognosis in lung adenocarcinoma patients. USP29 is unique among Snail1 deubiquitylases through exhibiting chemotherapy-induced upregulation. Mechanistically, oxidative stresses incurred by chemotherapy stimulate transcriptional activation of USP29. USP29 upregulation enhances the cancer stem cell-like characteristics in lung adenocarcinoma cells to promote tumorigenesis in athymic nude mice. Our findings uncover a novel mechanism by which chemotherapy induces cancer stemness and suggest USP29 as a potential therapeutic target to impede the development of chemoresistance and metastasis in lung adenocarcinoma.
- Publication
Cell Death & Disease, 2020, Vol 11, Issue 9, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-020-03008-5