USP29 enhances chemotherapy-induced stemness in non-small cell lung cancer via stabilizing Snail1 in response to oxidative stress

Yueguang Wu,Qingkai Yang,Duchuang Wang,Qingqing Zhang,Shanshan Wang,Taishu Wang,Yingqiu Zhang,Fang Liu,Dong Guo,Mohamed Y Zaky,Qianhui Sun,Shuyan Liu,Han Liu,Lu Xu,Jinrui Zhang,Yayun Zhang,Lijuan Zou,Qiong Li,Yang Zhang

doi:10.1038/s41419-020-03008-5

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.

Highlights

Cytotoxic chemotherapy represents one classic mode of cancer treatment, which effectively prolonged overall survivals of cancer patients over the decades
The zinc-finger transcription factor SNAI1, more commonly known as Snail[1], functions as a master regulator to promote the epithelial-mesenchymal transition (EMT) process through both repression of E-cadherin expression and the activated transcriptions of a panel of mesenchymal genes associated with invasive properties[6,7]
USP29 mRNA levels were observed to be upregulated in both A549 and H1299 cells, while those of DUB3, OTUB1, and USP27X mRNAs recorded no significant induction in either cell line (Fig. 6a–d). These findings indicate a unique feature of USP29 to respond to chemotherapeutic agents among various Snail[1] DUBs in lung adenocarcinoma cells

Summary

Introduction

Cytotoxic chemotherapy represents one classic mode of cancer treatment, which effectively prolonged overall survivals of cancer patients over the decades. Its adverse side effects are mainly considered as cytotoxicityrelated, accumulating evidences have started to associate chemotherapeutic treatments with enhanced cancer stemness that leads to drug resistance and tumor dissemination[1]. Convincing evidences have been demonstrated that both host and tumor cells are capable of eliciting responses to promote tumor survival, cultivate chemoresistance, and assist metastasis[1,2,3,4,5]. The zinc-finger transcription factor SNAI1, more commonly known as Snail[1], functions as a master regulator to promote the epithelial-mesenchymal transition (EMT) process through both repression of E-cadherin expression and the activated transcriptions of a panel of mesenchymal genes associated with invasive properties[6,7]. Snail[1] expression was closely implicated in the progression of multiple types of Official journal of the Cell Death Differentiation Association

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Results

Conclusion