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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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DUSP6 regulates Notch1 signalling in colorectal cancer
Chin Wen Png1,2,3, Madhushanee Weerasooriya1,2,3, Heng Li1,2,3
1Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore.
Nature Communications
|November 21, 2024
Summary
Dual-specificity phosphatase 6 (DUSP6) dephosphorylates Notch1, stabilizing its intracellular domain (NTM) and promoting colorectal cancer (CRC) cell growth. DUSP6 inhibition may offer a therapeutic strategy for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Notch1 signaling is crucial in cancer development.
- Phosphorylation regulates Notch1 activity via its intracellular domain (NTM).
- The role of phosphatases in dephosphorylating NTM remains largely unknown.
Purpose of the Study:
- To investigate if DUSP6 acts as a phosphatase for Notch1.
- To determine DUSP6's role in regulating NTM stability and transcriptional activity.
- To elucidate DUSP6's influence on colorectal cancer (CRC) development.
Main Methods:
- Assessed DUSP6's phosphatase activity towards Notch1 in human CRC cells.
- Correlated DUSP6 expression with NTM levels and CRC cell proliferation in vitro and in vivo.
- Analyzed the impact of DUSP6 deficiency on CRC development in mouse models.
- Investigated the molecular mechanism of DUSP6-mediated NTM dephosphorylation at phospho-Y2116.
Main Results:
- DUSP6 dephosphorylates Notch1 at Y2116, stabilizing NTM.
- Elevated DUSP6 expression in CRC cells increases NTM stability and transcriptional activity.
- Increased NTM levels promote CRC cell proliferation in vitro and in vivo.
- High tumoral DUSP6 expression correlates with poorer patient survival.
- DUSP6 deficiency reduces CRC development in mice.
Conclusions:
- DUSP6 functions as a phosphatase for Notch1, regulating NTM stability.
- DUSP6 promotes CRC cell proliferation by stabilizing NTM and enhancing Notch1 target gene expression.
- DUSP6 is a potential therapeutic target for colorectal cancer.
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