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Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
Yang Zheng1,2, An Song1,2, Chundi Wang1,2
1Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Abstract:
Our group previously identified that the NOTCH1 Abruptex domain contains the most mutations in Chinese OSCC patients, including a hotspot mutation (C1133Y). FBXW7 is an E3 ubiquitin ligase that regulates a network of proteins, including NOTCH1, via degradation. In this study, we first described the co-localization of isoform specific FBXW7-FBXW7β and NOTCH1C1133Y mutation in the same cytoplasmic sites. Gain- and loss-of-function assays were performed to examine the tumor suppressor role of FBXW7β in the proliferation and invasion of OSCC cells. The co-expression of NOTCH1C1133Y and FBXW7β significantly attenuated tumor growth. Meanwhile, FBXW7β reversed the oncogenic phenotype and the activation of the AKT/ERK/NFκB pathway induced by NOTCH1C1133Y mutation. FBXW7β downregulated the stability of NOTCH1C1133Y protein and promoted protein ubiquitination. This was the first time that we selected a NOTCH1 hotspot mutation detected in clinical samples and identified the function of FBXW7β that mediated NOTCH1 mutation degradation in OSCC. The newly identified interaction between FBXW7β and NOTCH1C1133Y protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy.
Insights
FBXW7β acts as a tumor suppressor in oral squamous cell carcinoma (OSCC) by degrading the mutated NOTCH1C1133Y protein. This interaction inhibits OSCC cell proliferation and invasion, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Signaling
Background:
- The NOTCH1 Abruptex domain harbors frequent mutations in Chinese oral squamous cell carcinoma (OSCC) patients, notably the C1133Y hotspot.
- FBXW7, an E3 ubiquitin ligase, targets proteins including NOTCH1 for degradation, playing a role in cellular regulation.
Purpose of the Study:
- To investigate the functional role of FBXW7β in OSCC, specifically its interaction with the NOTCH1C1133Y mutation.
- To determine if FBXW7β exhibits tumor suppressor activity against OSCC progression driven by NOTCH1 mutations.
Main Methods:
- Co-localization studies of FBXW7β and NOTCH1C1133Y in OSCC cells.
- Gain- and loss-of-function assays to assess the impact of FBXW7β on OSCC cell proliferation and invasion.
- Analysis of signaling pathways (AKT/ERK/NFκB) and protein stability/ubiquitination.
Main Results:
- FBXW7β and NOTCH1C1133Y were found to co-localize in the cytoplasm.
- FBXW7β expression attenuated OSCC tumor growth, proliferation, and invasion.
- FBXW7β reversed the oncogenic effects of NOTCH1C1133Y by downregulating its stability and promoting ubiquitination, thereby inhibiting AKT/ERK/NFκB pathway activation.
Conclusions:
- FBXW7β acts as a tumor suppressor in OSCC by mediating the degradation of the NOTCH1C1133Y hotspot mutation.
- The interaction between FBXW7β and NOTCH1C1133Y provides novel therapeutic insights for OSCC, particularly concerning Abruptex domain mutations.
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