OTUD7B suppresses Smac mimetic-induced lung cancer cell invasion and migration via deubiquitinating TRAF3
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RESEARCH
(2020) 39:244
Open Access
OTUD7B suppresses Smac mimetic-induced lung cancer cell invasion and migration via deubiquitinating TRAF3 Boxiang Zhang1†, Chengcheng Yang2†, Rui Wang1, Jie Wu1, Yunfeng Zhang1, Dapeng Liu1, Xin Sun1, Xiang Li1, Hong Ren1* and Sida Qin1*
Abstract Background: Smac mimetics are a type of drug that can induce apoptosis by antagonizing IAP family members in cancer treatment. However, a recent study showed that Smac mimetics can trigger cell invasion and migration in cancer cells by activating the NF-κB pathway. Methods: We assessed lung cancer cell elongation, invasion and migration under treatment with the Smac mimetic LCL161. Functional analyses (in vitro and in vivo) were performed to detect the contribution of NIK and OTUD7B to LCL161-induced cell invasion and migration. The role of OTUD7B in regulation of the TRAF3/NIK/NF-κB pathway under LCL161 treatment was analysed by immunoblotting, immunoprecipitation, luciferase and ubiquitin assays, shRNA silencing and plasmid overexpression. Expression levels of OTUD7B, NIK and TRAF3 in tissue samples from lung cancer patients were examined by immunohistochemistry. Results: We found that LCL161 stimulates lung cancer cell elongation, invasion and migration at non-toxic concentrations. Mechanistically, LCL161 results in NIK accumulation and activates the non-canonical rather than the canonical NF-κB pathway to enhance the transcription of target genes, such as IL-2 and MMP-9. Importantly, knockdown of NIK dramatically suppresses LCL161-induced cell invasion and migration by reducing the proteolytic processing of p100 to p52 and target gene transcription. Interestingly, we discovered that OTUD7B increases TRAF3 and decreases NIK to inhibit the non-canonical NF-κB pathway and that overexpression of OTUD7B suppresses LCL161-induced cell invasion and migration. Notably, OTUD7B directly binds to TRAF3 rather than to NIK and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing NIK accumulation and NF-κB pathway activation. Furthermore, the OTU domain of OTUD7B is required for the inhibition of LCL161-induced cell invasion and migration, as demonstrated by transfection of the C194S/H358R(CH) mutant OTUD7B. Finally, we investigated whether OTUD7B inhibits LCL161-induced lung cancer cell intrapulmonary metastasis in vivo, and our analysis of clinical samples was consistent with the above findings. (Continued on next page)
* Correspondence: [email protected]; [email protected] † Boxiang Zhang and Chengcheng Yang contributed equally to this work. 1 Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an 710061, Shaanxi, China Full list of author information is available at the end of the article
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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