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TRIM14 suppressed the progression of NSCLC via hexosamine biosynthesis pathway
Sisi Wei1, Meiling Ai2,3, Yuan Zhan4
1Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
Abstract:
Tripartite Motif 14 (TRIM14) is an oncoprotein that belongs to the E3 ligase TRIM family, which is involved in the progression of various tumors except for non-small cell lung carcinoma (NSCLC). However, little is currently known regarding the function and related mechanisms of TRIM14 in NSCLC. Here, we found that the TRIM14 protein was downregulated in lung adenocarcinoma tissues compared with the adjacent tissues, which can suppress tumor cell proliferation and migration both in vitro and in vivo. Moreover, TRIM14 can directly bind to glutamine fructose-6-phosphate amidotransferase 1 (GFAT1), which in turn results in the degradation of GFAT1 and reduced O-glycosylation levels. GFAT1 is a key enzyme in the rate-limiting step of the hexosamine biosynthetic pathway (HBP). Replenishment of N-acetyl-d-glucosamine can successfully reverse the inhibitory effect of TRIM14 on the NSCLC cell growth and migration as expected. Collectively, our data revealed that TRIM14 suppressed NSCLC cell proliferation and migration through ubiquitination and degradation of GFAT1, providing a new regulatory role for TRIM14 on HBP.
Insights
Tripartite Motif 14 (TRIM14) is downregulated in lung cancer, suppressing tumor growth. It targets GFAT1 for degradation, impacting the hexosamine biosynthetic pathway (HBP) and reducing O-glycosylation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tripartite Motif 14 (TRIM14) is an E3 ligase implicated in various cancers.
- Its role in non-small cell lung carcinoma (NSCLC) remains largely unexplored.
Purpose of the Study:
- To investigate the function and regulatory mechanisms of TRIM14 in NSCLC.
- To elucidate the molecular pathways by which TRIM14 influences tumor progression.
Main Methods:
- Comparative analysis of TRIM14 expression in lung adenocarcinoma and adjacent tissues.
- In vitro and in vivo studies to assess the impact of TRIM14 on tumor cell proliferation and migration.
- Co-immunoprecipitation assays to identify TRIM14 binding partners.
- Western blotting to evaluate protein levels and ubiquitination.
- Functional assays involving N-acetyl-d-glucosamine replenishment.
Main Results:
- TRIM14 protein was found to be downregulated in lung adenocarcinoma tissues.
- Reduced TRIM14 expression suppressed tumor cell proliferation and migration in vitro and in vivo.
- TRIM14 directly binds to glutamine fructose-6-phosphate amidotransferase 1 (GFAT1), leading to its degradation.
- TRIM14 downregulation resulted in decreased O-glycosylation levels.
- Restoring N-acetyl-d-glucosamine levels reversed the inhibitory effects of TRIM14 on NSCLC cell growth and migration.
Conclusions:
- TRIM14 acts as a tumor suppressor in NSCLC by inhibiting cell proliferation and migration.
- TRIM14 suppresses NSCLC progression via ubiquitination and degradation of GFAT1, a key enzyme in the hexosamine biosynthetic pathway (HBP).
- This study reveals a novel regulatory role for TRIM14 in the HBP pathway within the context of NSCLC.
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