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Melanoma Glycome Regulates the Pro-Oncogenic Properties of Extracellular Galectin-3
Norhan B B Mohammed1, Rajib K Shil2, Charles J Dimitroff2
1The Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA.
Abstract:
Metastatic melanoma is an aggressive skin cancer with a five-year survival rate of only 35%. Despite recent advances in immunotherapy, there is still an urgent need for the development of innovative therapeutic approaches to improve clinical outcomes of patients with metastatic melanoma. Prior research from our laboratory revealed that loss of the I-branching enzyme β1,6 N-acetylglucosaminyltransferase 2 (GCNT2), with consequent substitution of melanoma surface I-branched poly-N-acetyllactosamines (poly-LacNAcs) with i-linear poly-LacNAcs, is implicated in driving melanoma metastasis. In the current study, we explored the role of galectin-3 (Gal-3), a lectin that avidly binds surface poly-LacNAcs, in dictating melanoma aggressive behavior. Our results show that Gal-3 favors binding to i-linear poly-LacNAcs, while enforced GCNT2/I-branching disrupts this interaction, thereby suppressing Gal-3-dependent malignant characteristics, including extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway activation, BCL2 expression, cell proliferation, and migration. This report establishes the crucial role of extracellular Gal-3 interactions with i-linear glycans in promoting melanoma cell aggressiveness, placing GCNT2 as a tumor suppressor protein and suggesting both extracellular Gal-3 and i-linear glycans as potential therapeutic targets for metastatic melanoma.
Insights
Loss of GCNT2 in melanoma promotes metastasis by altering cell surface glycans, enabling Galectin-3 binding and driving cancer progression. Restoring GCNT2 suppresses these aggressive traits, highlighting therapeutic potential.
Area of Science:
- Glycobiology
- Cancer Biology
- Molecular Oncology
Background:
- Metastatic melanoma has a poor prognosis, necessitating novel therapeutic strategies.
- Loss of β1,6 N-acetylglucosaminyltransferase 2 (GCNT2) leads to i-linear poly-N-acetyllactosamines (poly-LacNAcs) on melanoma cells, promoting metastasis.
- Galectin-3 (Gal-3) binds to poly-LacNAcs and influences cancer cell behavior.
Purpose of the Study:
- To investigate the role of Galectin-3 (Gal-3) in mediating melanoma aggressiveness.
- To determine how Gal-3 interaction with specific glycan structures influences melanoma progression.
Main Methods:
- Analysis of Gal-3 binding to i-linear versus I-branched poly-LacNAcs.
- Assessment of GCNT2 expression and its impact on Gal-3 interactions.
- Evaluation of Gal-3-dependent signaling pathways (ERK/MAPK), BCL2 expression, proliferation, and migration.
Main Results:
- Gal-3 preferentially binds to i-linear poly-LacNAcs found on melanoma cells with low GCNT2 activity.
- Enforced GCNT2 expression and I-branching of poly-LacNAcs disrupt Gal-3 binding.
- Disruption of Gal-3 binding suppresses melanoma cell proliferation, migration, ERK/MAPK pathway activation, and BCL2 expression.
Conclusions:
- Extracellular Gal-3 interaction with i-linear glycans is critical for promoting melanoma aggressiveness.
- GCNT2 functions as a tumor suppressor by preventing these pro-metastatic interactions.
- Targeting Gal-3 or i-linear glycans presents a potential therapeutic strategy for metastatic melanoma.
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