Next Article in Journal
Prediction of Drug Efficacy in Colon Cancer Preclinical Models Using a Novel Ranking Method of Gene Expression
Next Article in Special Issue
Ubiquitin-Specific Protease 21 Promotes Colorectal Cancer Metastasis by Acting as a Fra-1 Deubiquitinase
Previous Article in Journal
Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer
Open AccessArticle

Epigenetic Silencing of Ubiquitin Specific Protease 4 by Snail1 Contributes to Macrophage-Dependent Inflammation and Therapeutic Resistance in Lung Cancer

1
Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
2
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
3
Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 148; https://doi.org/10.3390/cancers12010148
Received: 3 December 2019 / Revised: 28 December 2019 / Accepted: 6 January 2020 / Published: 8 January 2020
(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)
There is a positive feedback loop driving tumorigenesis and tumor growth through coordinated regulation of epigenetics, inflammation, and stemness. Nevertheless, the molecular mechanism linking these processes is not well understood. In this study, we analyzed the correlation of de-ubiquitinases (DUBs) expression with survival data from the OncoLnc database. Among the DUBs analyzed, ubiquitin specific protease 4 (USP4) had the lowest negative Cox coefficient. Low expression of USP4 was associated with poor survival among lung cancer patients and was inversely correlated with expression of stemness and inflammation markers. Expression of USP4 were reduced at more advanced stages of lung cancer. Mechanistically, expression of USP4 was downregulated in snail1-overexpressing and stemness-enriched lung cancer cells. Snail1 was induced in lung cancer cells by interaction with macrophages, and epigenetically suppressed USP4 expression by promoter methylation. Stable knockdown of USP4 in lung cancer cells enhanced inflammatory responses, stemness properties, chemotherapy resistance, and the expression of molecules allowing escape from immunosurveillance. Further, mice injected with USP4 knockdown lung cancer cells demonstrated enhanced tumorigenesis and tumor growth. These results reveal that the Snail1-mediated suppression of USP4 is a potential mechanism to orchestrate epigenetic regulation, inflammation and stemness for macrophage-promoted tumor progression. View Full-Text
Keywords: deubiquitination; Snail1; inflammation; stemness; epigenetic regulation deubiquitination; Snail1; inflammation; stemness; epigenetic regulation
Show Figures

Graphical abstract

MDPI and ACS Style

Lai, C.-Y.; Yeh, D.-W.; Lu, C.-H.; Liu, Y.-L.; Chuang, Y.-C.; Ruan, J.-W.; Kao, C.-Y.; Huang, L.-R.; Chuang, T.-H. Epigenetic Silencing of Ubiquitin Specific Protease 4 by Snail1 Contributes to Macrophage-Dependent Inflammation and Therapeutic Resistance in Lung Cancer. Cancers 2020, 12, 148.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop