LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction
Yawen Ma1, Lihua Wang1, Fanglin He1
1Department of Ophthalmology, Ninth People's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Cancer Letters
|March 6, 2021
Summary
Lactamase β (LACTB), a tumor suppressor, is downregulated in melanoma. Overexpressing LACTB inhibits melanoma cell growth and metastasis by inactivating the YAP protein, presenting a new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Advanced melanoma, particularly uveal melanoma, has limited treatment options.
- The tumor suppressor Lactamase β (LACTB) role in melanoma is currently unknown.
- Identifying novel therapeutic targets is crucial for improving melanoma patient outcomes.
Purpose of the Study:
- To investigate the biological function and mechanism of Lactamase β (LACTB) in melanoma.
- To explore the potential of LACTB as a therapeutic target for melanoma treatment.
- To elucidate the signaling pathway involving LACTB and its regulation in melanoma progression.
Main Methods:
- Quantitative analysis of LACTB expression in melanoma tissues and cell lines.
- In vitro experiments assessing the effects of LACTB overexpression on melanoma cell proliferation, migration, and invasion.
- Western blotting and co-immunoprecipitation assays to investigate the interaction between LACTB, YAP, PP1A, and LATS1.
- In vivo studies using xenograft models to evaluate the impact of LACTB on tumor growth and metastasis.
- Chromatin immunoprecipitation assays to determine SOX10 binding to the LACTB promoter.
Main Results:
- LACTB expression is significantly lower in melanoma tissues and cell lines compared to normal tissues.
- Overexpression of LACTB inhibits melanoma cell proliferation, migration, and invasion in vitro.
- LACTB suppresses melanoma progression by inhibiting the activity of yes-associated protein (YAP), leading to increased YAP phosphorylation and nuclear exclusion.
- LACTB directly binds to PP1A, reducing PP1A-YAP interaction and YAP dephosphorylation in a LATS1-independent manner.
- SOX10 negatively regulates LACTB transcription by binding to its promoter.
- LACTB overexpression suppresses tumor growth and lung metastasis in vivo.
- Phosphorylation-defective YAP mutants can reverse LACTB-mediated tumor suppression.
Conclusions:
- LACTB functions as a tumor suppressor in melanoma by inhibiting YAP activity.
- A novel SOX10/LACTB/PP1A signaling cascade regulates YAP inactivation and melanoma progression.
- LACTB represents a promising therapeutic target for advanced melanoma, including uveal melanoma.
Keywords:
Catalytic subunit alpha of protein phosphatase-1DephosphorylationLactamase betaMelanomaYes-associated proteinMore Related Videos
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