The deubiquitylase UCHL3 maintains cancer stem-like properties by stabilizing the aryl hydrocarbon receptor
Open Access
- 17 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Signal Transduction and Targeted Therapy
- Vol. 5 (1), 1-14
- https://doi.org/10.1038/s41392-020-0181-3
Abstract
Cancer stem cells (CSCs) exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy. Aryl hydrocarbon receptor (AhR) expression varies among non-small cell lung cancers (NSCLCs), and the mechanisms that support abnormal AhR expression in CSCs remain elusive. Here, we identified ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, as a bona fide deubiquitylase of the AhR in NSCLC. UCHL3 was shown to interact with, deubiquitylate, and stabilize AhR in a manner dependent on its deubiquitylation activity. Moreover, we showed that UCHL3 promotes the stem-like characteristics and potent tumorigenic capacity of NSCLC cells. UCHL3 increased AhR stability and the binding of AhR to the promoter regions of the "stemness" genes ATP-binding cassette subfamily G member 2 (ABCG2), KLF4, and c-Myc. Depletion of UCHL3 markedly downregulated the "stemness" genes ABCG2, KLF4, and c-Myc, leading to the loss of self-renewal and tumorigenesis in NSCLCs. Furthermore, the UCHL3 inhibitor TCID induced AhR degradation and exhibited significantly attenuated efficacy in NSCLC cells with stem cell-like properties. Additionally, UCHL3 was shown to indicate poor prognosis in patients with lung adenocarcinoma. In general, our results reveal that the UCHL3 deubiquitylase is pivotal for AhR protein stability and a potential target for NSCLC-targeted therapy.Funding Information
- National Natural Science Foundation of China (81874139, 81672787, 81672308, 81672991)
- National Basic Research Program of China
This publication has 67 references indexed in Scilit:
- Targeting deubiquitinating enzymes in cancer stem cellsCancer Cell International, 2017
- Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per - Arnt - sim (bHLH/PAS) family of “sensors” of foreign and endogenous signalsProgress in Lipid Research, 2017
- The comparative effects of diethyldithiocarbamate-copper complex with established proteasome inhibitors on expression levels of CYP1A2/3A4 and their master regulators, aryl hydrocarbon and pregnane X receptor in primary cultures of human hepatocytesFundamental & Clinical Pharmacology, 2016
- Ubiquitin C-terminal hydrolase-L3 regulates EMT process and cancer metastasis in prostate cell linesBiochemical and Biophysical Research Communications, 2014
- Mechanisms Governing Metastatic Dormancy and ReactivationCell, 2013
- Epigenetic Reprogramming in CancerScience, 2013
- CD44+ Cancer Stem-Like Cells in EBV-Associated Nasopharyngeal CarcinomaPLOS ONE, 2012
- Ah Receptor Antagonism Represses Head and Neck Tumor Cell Aggressive PhenotypeMolecular Cancer Research, 2012
- p23 co-chaperone protects the aryl hydrocarbon receptor from degradation in mouse and human cell linesBiochemical Pharmacology, 2012
- Defining the Human Deubiquitinating Enzyme Interaction LandscapeCell, 2009