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FBXW7 Targets the SPT6-ΔNp63 Axis for Degradation to Inhibit Esophageal Tumorigenesis Induced by 4-Nitroquinoline
Jiagui Zhang1,2, Lu Yin1,2, Xiahong You1,2
1Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China.
Abstract:
FBXW7 (F-box and WD repeat domain-containing 7) is a classic tumor suppressor that promotes ubiquitylation and degradation of various oncoproteins. Although its tumor suppressor role in many types of cancers has been established, whether and how FBXW7 regulates in vivo esophageal tumorigenesis was previously unknown. Here, we report, using genetically modified mouse models, that Fbxw7 inhibits esophageal tumorigenesis induced by the carcinogen 4NQO (4-nitroquinoline N-oxide), but not by Pik3CaE545K (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), a frequently mutated gene in human esophageal squamous cell carcinoma (ESCC). Mechanistically, FBXW7 depletion causes the accumulation of SPT6 (suppressor of Ty6), a transcriptional elongation factor, which is a novel substrate of FBXW7. SPT6 acts as a transcriptional co-activator of ΔNp63, which is also a substrate of FBXW7 in ESCC cells. Both SPT6 and ΔNp63, accumulated upon FBXW7 knockdown, contribute to the proliferation of ESCC cells. In clinical human ESCC tissues, the protein levels of SPT6 and FBXW7 are inversely correlated, and high SPT6 levels with low FBXW7 levels predict poorer patient survival. Collectively, FBXW7 acts as a tumor suppressor in ESCC by promoting the degradation of both SPT6 and ΔNp63, and the SPT6-ΔNp63 axis may serve as a therapeutic target for ESCC.
Insights
F-box and WD repeat domain-containing 7 (FBXW7) suppresses esophageal cancer by degrading SPT6 and ΔNp63. Loss of FBXW7 promotes tumor growth, indicating the SPT6-ΔNp63 pathway as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- F-box and WD repeat domain-containing 7 (FBXW7) is a known tumor suppressor.
- Its role in in vivo esophageal tumorigenesis was previously uncharacterized.
Purpose of the Study:
- To investigate the role of FBXW7 in esophageal tumorigenesis.
- To elucidate the molecular mechanisms by which FBXW7 regulates esophageal squamous cell carcinoma (ESCC).
Main Methods:
- Genetically modified mouse models were used to study esophageal tumorigenesis.
- FBXW7 depletion and its effects on protein accumulation were analyzed.
- Correlation between SPT6, FBXW7, and patient survival in human ESCC tissues was assessed.
Main Results:
- FBXW7 inhibits 4-nitroquinoline N-oxide-induced esophageal tumorigenesis but not Pik3CaE545K-induced tumorigenesis.
- FBXW7 depletion leads to the accumulation of SPT6, a novel substrate and transcriptional co-activator of ΔNp63.
- Both accumulated SPT6 and ΔNp63 contribute to ESCC cell proliferation, and their levels are inversely correlated with FBXW7 in clinical samples, predicting poorer survival.
Conclusions:
- FBXW7 functions as a tumor suppressor in ESCC by mediating the degradation of SPT6 and ΔNp63.
- The SPT6-ΔNp63 axis represents a potential therapeutic target for ESCC.
