Ubiquitin-specific protease 22 is critical to in vivo angiogenesis, growth and metastasis of non-small cell lung cancer.
BACKGROUND
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.
['Zhang|Keqiang|K|0000-0002-4210-4401', 'Yang|Lu|L|', 'Wang|Jinhui|J|', 'Sun|Ting|T|', 'Guo|Yuming|Y|', 'Nelson|Rebecca|R|', 'Tong|Tommy R|TR|', 'Pangeni|Rajendra|R|', 'Salgia|Ravi|R|', 'Raz|Dan J|DJ|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D002289:Carcinoma, Non-Small-Cell Lung D049109:Cell Proliferation D002945:Cisplatin D004260:DNA Repair D004273:DNA, Neoplasm D004195:Disease Models, Animal D005260:Female D006801:Humans D053631:Interleukin Receptor Common gamma Subunit D008114:Liver Neoplasms, Experimental D008175:Lung Neoplasms D008297:Male D051379:Mice D016688:Mice, Inbred NOD D018345:Mice, Knockout D016513:Mice, SCID D008875:Middle Aged D009362:Neoplasm Metastasis D009389:Neovascularization, Pathologic D015398:Signal Transduction D014407:Tumor Cells, Cultured D043222:Ubiquitin Thiolesterase
Angiogenesis Growth Metastasis Non-small cell lung cancer (NSCLC) USP22 Epithelial-mesenchymal transition (EMT) Therapeutic target