E3 ligase TRIM15 facilitates non-small cell lung cancer progression through mediating Keap1-Nrf2 signaling pathway

Abstract

Background Recent studies have indicated that some members of the tripartite motif (TRIM) proteins function as important regulators for non-small cell lung cancer (NSCLC), However, the regulatory mechanism underpinning aberrant expression of TRIM in NSCLC remains unclear. Here we report that TRIM15 plays important roles in NSCLC progression through modulating Keap1-Nrf2 signaling pathway. Methods TRIM15 expression was evaluated by western blot analysis, tissue microarray-based immunohistochemistry analysis. The interactions between TRIM15 and Keap1 were analyzed by co-immunoprecipitation (Co-IP) and immunofluorescence co-localization assay. The correlation between TRIM15 and Keap1 was measured by Co-IP and ubiquitination analysis in vitro. Gain- and lost-of-function experiments were used to detect TRIM15 promotes proliferation and invasion of NSCLC cells both in vitro and vivo. Results Here, we revealed that TRIM15 was frequently upregulated in NSCLC samples and associated with poor prognosis. Functionally, TRIM15 knockdown resulted in decreased cancer cell proliferation and metastasis, whereas ectopic TRIM15 expression facilitated tumor cancer cell proliferation and metastasis in vitro and in vivo. Moreover, TRIM15 promoted cell proliferation and metastasis depends on its E3 ubiquitin ligase. Mechanistically, TRIM15 directly targeted Keap1 by ubiquitination and degradation, the principal regulator of Nrf2 degradation, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant response and tumor progression. Conclusions Therefore, our study characterizes the pivotal roles of TRIM15 promotes NSCLC progression via Nrf2 stability mediated by promoting Keap1 ubiquitination and degradation and could be a valuable prognostic biomarker and a potential therapeutic target in NSCLC.

TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs

“…We previously reported that TRIM15 promotes APOA1 ubiquitination and degradation in pancreatic cancer [ 11 ]. Liang et al reported that TRIM15 directly targets Keap1 for degradation [ 12 ]. In addition to enhancing the degradation of its substrates, TRIM15 has also been reported to mediate K63-linked ubiquitination of its substrates, such as TAK1 [ 40 ] and ERK1/2 [ 24 ], and modulate the function of these proteins.…”

“…The tripartite motif (TRIM) family member TRIM15 acts as an E3 ligase to mediate the polyubiquitination of substrates in cells [ 11 ]. Dysregulation of TRIM15 contributes to tumor progression in pancreatic cancer and non-small cell lung cancer [ 11 , 12 ]. In this study, we found that TRIM15 was abnormally upregulated in liver cancer cells after treated with TKIs and that this upregulation of TRIM15 contributed to TKI resistance in liver cancer cells.…”

Telomere-related gene risk model for prognosis and drug treatment efficiency prediction in kidney cancer

“…Tripartite Motif Containing 15 (TRIM15) encodes a member of the Tripartite motif family, which could exhibit E3 ubiquitin ligase activity. TRIM15 could regulate the Wnt/b-catenin signaling pathway and Keap1-Nrf2 pathway and mediate the ubiquitination of APOA1 and ERK to promote the development and progression of cancers such as non-small cell lung cancer, esophageal squamous cell carcinoma, and pancreatic cancer (35)(36)(37). NIMA Related Kinase 6 (NEK6) encodes a kinase, which plays multiple roles in the tumor, including suppression of tumor cell senescence and facilitation of breast cancer cell proliferation.…”

TRIM family contribute to tumorigenesis, cancer development, and drug resistance

“…Moreover, TRIM22 was found to inhibit the Warburg effect in osteosarcoma cells [ 101 ]. In another study, TRIM15 was identified to promote NSCLC progression via Nrf2 stability mediated by promoting Keap1 (Kelch-like ECH associated protein 1) ubiquitination and degradation [ 94 ]. Keap1 is an E3 ubiquitin ligase, which tightly regulates the activity of Nrf2 by targeting it for ubiquitination.…”

“…The Notch, AMPK, MAPK, and YAP signaling pathways have also been reported to play vital roles in cancer. Knockdown a crucial coactivator of Notch receptors and signal transmission and function, decreases the expression of TRIM13, TRIM32, TRIM44, and TRIM59 especially in T-ALL [ 94 ]. The activation of MAPK enhances TRIM2 protein levels and affectes its binding with Bim, resulting in reduced Bim in tamoxifen-resistant breast cancer cells [ 256 ].…”