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Article: Ubiquitin-specific protease 22 is critical to in vivo angiogenesis, growth and metastasis of non-small cell lung cancer

TitleUbiquitin-specific protease 22 is critical to in vivo angiogenesis, growth and metastasis of non-small cell lung cancer
Authors
KeywordsNon-small cell lung cancer (NSCLC)
USP22
Angiogenesis
Epithelial-mesenchymal transition (EMT)
Growth
Issue Date2019
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.biosignaling.com/home/
Citation
Cell Communication and Signaling, 2019, v. 17 n. 1, p. article no. 167 How to Cite?
AbstractBackground: Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor differentiation, cancer stemness, and enhanced malignancy of non-small cell lung cancer (NSCLC). Herein, we investigated the biological significance and therapeutic implications of ubiquitin-specific protease 22 (USP22), an H2Bub1 deubiquitinase, in non-small cell lung cancer (NSCLC). Methods: USP22 expression and its clinical relevance were assessed in NSCLC patients. The effects of USP22 knockout on sensitivity to cisplatin and irradiation, and growth, metastasis of NSCLC xenografts, and survival of cancer-bearing mice were investigated. The underlying mechanisms of targeting USP22 were explored. Results: Overexpression of USP22 was observed in 49.0% (99/202) of NSCLC tissues; higher USP22 immunostaining was found to be associated with enhanced angiogenesis and recurrence of NSCLC. Notably, USP22 knockout dramatically suppressed in vitro proliferation, colony formation; and angiogenesis, growth, metastasis of A549 and H1299 in mouse xenograft model, and significantly prolonged survival of metastatic cancer-bearing mice. Furthermore, USP22 knockout significantly impaired non-homologous DNA damage repair capacity, enhanced cisplatin and irradiation-induced apoptosis in these cells. In terms of underlying mechanisms, RNA sequencing and gene ontology enrichment analysis demonstrated that USP22 knockout significantly suppressed angiogenesis, proliferation, EMT, RAS, c-Myc pathways, concurrently enhanced oxidative phosphorylation and tight junction pathways in A549 and H1299 NSCLC cells. Immunoblot analysis confirmed that USP22 knockout upregulated E-cadherin, p16; reduced ALDH1A3, Cyclin E1, c-Myc, and attenuated activation of AKT and ERK pathways in these cells. Conclusions: Our findings suggest USP22 plays critical roles in the malignancy and progression of NSCLC and provide rationales for targeting USP22, which induces broad anti-cancer activities, as a novel therapeutic strategy for NSCLC patient. Keywords: Angiogenesis; Epithelial-mesenchymal transition (EMT); Growth; Metastasis; Non-small cell lung cancer (NSCLC); Therapeutic target; USP22.
Persistent Identifierhttp://hdl.handle.net/10722/285269
ISSN
2018 Impact Factor: 5.111
2015 SCImago Journal Rankings: 1.860
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, K-
dc.contributor.authorYang, L-
dc.contributor.authorWang, J-
dc.contributor.authorSun, T-
dc.contributor.authorGuo, Y-
dc.contributor.authorNelson, R-
dc.contributor.authorTong, TR-
dc.contributor.authorPangeni, R-
dc.contributor.authorSalgia , R-
dc.contributor.authorRaz, DJ-
dc.date.accessioned2020-08-18T03:51:52Z-
dc.date.available2020-08-18T03:51:52Z-
dc.date.issued2019-
dc.identifier.citationCell Communication and Signaling, 2019, v. 17 n. 1, p. article no. 167-
dc.identifier.issn1478-811X-
dc.identifier.urihttp://hdl.handle.net/10722/285269-
dc.description.abstractBackground: Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor differentiation, cancer stemness, and enhanced malignancy of non-small cell lung cancer (NSCLC). Herein, we investigated the biological significance and therapeutic implications of ubiquitin-specific protease 22 (USP22), an H2Bub1 deubiquitinase, in non-small cell lung cancer (NSCLC). Methods: USP22 expression and its clinical relevance were assessed in NSCLC patients. The effects of USP22 knockout on sensitivity to cisplatin and irradiation, and growth, metastasis of NSCLC xenografts, and survival of cancer-bearing mice were investigated. The underlying mechanisms of targeting USP22 were explored. Results: Overexpression of USP22 was observed in 49.0% (99/202) of NSCLC tissues; higher USP22 immunostaining was found to be associated with enhanced angiogenesis and recurrence of NSCLC. Notably, USP22 knockout dramatically suppressed in vitro proliferation, colony formation; and angiogenesis, growth, metastasis of A549 and H1299 in mouse xenograft model, and significantly prolonged survival of metastatic cancer-bearing mice. Furthermore, USP22 knockout significantly impaired non-homologous DNA damage repair capacity, enhanced cisplatin and irradiation-induced apoptosis in these cells. In terms of underlying mechanisms, RNA sequencing and gene ontology enrichment analysis demonstrated that USP22 knockout significantly suppressed angiogenesis, proliferation, EMT, RAS, c-Myc pathways, concurrently enhanced oxidative phosphorylation and tight junction pathways in A549 and H1299 NSCLC cells. Immunoblot analysis confirmed that USP22 knockout upregulated E-cadherin, p16; reduced ALDH1A3, Cyclin E1, c-Myc, and attenuated activation of AKT and ERK pathways in these cells. Conclusions: Our findings suggest USP22 plays critical roles in the malignancy and progression of NSCLC and provide rationales for targeting USP22, which induces broad anti-cancer activities, as a novel therapeutic strategy for NSCLC patient. Keywords: Angiogenesis; Epithelial-mesenchymal transition (EMT); Growth; Metastasis; Non-small cell lung cancer (NSCLC); Therapeutic target; USP22.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.biosignaling.com/home/-
dc.relation.ispartofCell Communication and Signaling-
dc.rightsCell Communication and Signaling. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectNon-small cell lung cancer (NSCLC)-
dc.subjectUSP22-
dc.subjectAngiogenesis-
dc.subjectEpithelial-mesenchymal transition (EMT)-
dc.subjectGrowth-
dc.titleUbiquitin-specific protease 22 is critical to in vivo angiogenesis, growth and metastasis of non-small cell lung cancer-
dc.typeArticle-
dc.identifier.emailTong, TR: ttongmd@hku.hk-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12964-019-0480-x-
dc.identifier.pmid31842906-
dc.identifier.pmcidPMC6916027-
dc.identifier.scopuseid_2-s2.0-85076701865-
dc.identifier.hkuros312736-
dc.identifier.volume17-
dc.identifier.issue1-
dc.identifier.spagearticle no. 167-
dc.identifier.epagearticle no. 167-
dc.publisher.placeUnited Kingdom-

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