TRIM13 inhibits cell proliferation and induces autophagy in lung adenocarcinoma by regulating KEAP1/NRF2 pathway

Abstract

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Tripartite motif 13 (TRIM13) is a member of TRIM protein family and is downregulated in multiple cancers, especially non-small cell lung cancers (NSCLC). In this study, we investigated anti-tumor mechanism of TRIM13 in non-small cell lung cancer tissues and cell lines. First, the mRNA and protein levels of TRIM13 in LUAD tissue and cells were measured. TRIM13 was overexpressed on LUAD cells to investigate the effects on cell proliferation, apoptosis, oxidative stress, p62 ubiquitination, and autophagy activation. Finally, mechanistic role of TRIM13 in regulating the Keap1/Nrf2 pathway was investigated. Results indicated that low level of TRIM13 mRNA and protein expression was found in LUAD tissue and cells. Overexpression of TRIM13 in LUAD cancer cells suppressed their proliferation, increased apoptosis, and oxidative stress, ubiquitinated p62, and activated autophagy via the RING finger domain of TRIM13. Furthermore, TRIM13 showed interaction with p62 and mediated its ubiquitination and degradation in LUAD cells. Mechanistically, TRIM13 exerted the tumor suppressor functions in LUAD cells by negatively regulating Nrf2 signaling and downstream antioxidants, which was further confirmed by in vivo data from xenografts. In conclusion, TRIM13 behaves like a tumor suppressor and triggers autophagy in LUAD cells by mediating p62 ubiquitination via KEAP1/Nrf2 pathway. Our findings provide a novel insight into targeted therapy plans for LUAD.