Tripartite motif protein 11 (TRIM11), an oncogene for human lung cancer via the DUSP6-mediated ERK1/2 signaling pathway

• Published in: Cancer biology & therapy Vol. 22; no. 4; pp. 324 - 332
• Main Authors: Wang, Xiao-Lin, Lu, Shi-Chun, Sun, Chao, Jin, Wei-Guo, Fan, Yi-Wei, Shu, Yu-Sheng, Shi, Hong-Can, Min, Ling-Feng
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03.04.2021
• Subjects: A549 Cells; Animals; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Cell Proliferation; Dual Specificity Phosphatase 6 - genetics; Dual Specificity Phosphatase 6 - metabolism; DUSP6; ERK1/2 pathway; Heterografts; Human non-small cell lung cancer; Humans; Lung Neoplasms - genetics; MAP Kinase Signaling System; Mice; Mice, Nude; Oncogenes; Research Paper; Signal Transduction; TRIM11; Tripartite Motif Proteins - genetics; Ubiquitin-Protein Ligases - genetics; Human non-small cell lung cancer; ERK1/2 pathway; DUSP6; TRIM11
• ISSN: 1538-4047; 1555-8576
• DOI: 10.1080/15384047.2021.1902912

Evidence suggests that Tripartite Motif Containing 11 (TRIM11) has pro-tumor activity in human non-small cell lung cancer (NSCLC). However, the roles and underlying mechanisms of TRIM11 in NSCLC have not yet been fully elucidated. In this work, human lung cancer cell lines (A549, H446, and H1975) were transfected with siRNA or lentiviruses to knockdown or overexpress TRIM11 and dual-specificity phosphatase 6 (DUSP6). The cell tumor response was assessed by determining the rate of proliferation, apoptosis, the uptake of 2-[N-(7-nitrobenz-2-oxa-1, 3-diaxol-4-yl) amino]-2-deoxyglucose (2-NBDG), and the secretion of lactic acid (LD). Dominant-negative (dn)-MEK1 was used to block the ERK1/2 pathway. The mechanism was investigated by assessing the protein levels of pyruvate kinase isozymes M2 (PKM2) and DUSP6, as well as the activation of ERK1/2 pathway. Our data confirmed the anti-cancer effect of siTRIM11 in human lung cancer by demonstrating inhibition of cancer cell proliferation, induction of apoptosis, prevention of 2-NBDG uptake, suppression of LD production, and prevention of lung cancer cell (A549) tumorigenicity in nude mice. The underlying mechanism involved the up-regulation of DUSP6 and the inhibition of ERK1/2 activity. Overexpression of TRIM11 induced tumorigenesis of NSCLC in vitro, and the activation of ERK1/2 was significantly reversed by DUSP6 overexpression or additional dn-MEK1 treatment. Interestingly, we confirmed TRIM11 as a deubiquitinase that regulated DUSP6 accumulation, indicating that lung cancer progression is regulated via the DUSP6-ERK1/2 pathway. In conclusion, TRIM11 is an oncogene in NSCLC, likely through the DUSP6-mediated ERK1/2 signaling pathway.