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整合的体内功能筛选和多组学分析确定α-2,3-唾液酸化对黑色素瘤维持至关重要。

Integrated in vivo functional screens and multiomics analyses identify α-2,3-sialylation as essential for melanoma maintenance.

作者信息

Agrawal Praveen, Chen Shuhui, de Pablos Ana, Vadlamudi Yellamandayya, Vand-Rajabpour Fatemeh, Jame-Chenarboo Faezeh, Kar Swarnali, Yanke Amanda Flores, Berico Pietro, de Vega Eleazar Miera Saenz, Darvishian Farbod, Osman Iman, Lujambio Amaia, Mahal Lara K, Hernando Eva

机构信息

Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.

Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.

出版信息

Sci Adv. 2025 Jul 4;11(27):eadg3481. doi: 10.1126/sciadv.adg3481.

DOI:10.1126/sciadv.adg3481
PMID:40614178
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12227053/
Abstract

Aberrant glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma maintenance, we conducted an in vivo growth screen with a pooled short hairpin RNA library of glycosyltransferases, lectin microarray profiling of benign nevus and melanoma samples, and mass spectrometry-based glycoproteomics. We found that α-2,3-sialyltransferases ST3GAL1 and ST3GAL2 and corresponding α-2,3-linked sialosides are up-regulated in melanoma compared to nevi and are essential for melanoma growth. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter SLC3A2/CD98hc. CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its prosurvival effect on melanoma are dependent upon α-2,3-sialylation mediated by ST3GAL1 and ST3GAL2. Our studies reveal α-2,3-sialosides functionally contributing to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as therapeutic targets in melanoma.

摘要

异常糖基化是癌症生物学的一个标志，糖基化改变会影响黑色素瘤进展的多个方面。为了确定黑色素瘤维持所必需的糖基转移酶、聚糖和糖蛋白，我们使用糖基转移酶的短发夹RNA文库进行了体内生长筛选，对良性痣和黑色素瘤样本进行了凝集素微阵列分析，并进行了基于质谱的糖蛋白质组学研究。我们发现，与痣相比，α-2,3-唾液酸转移酶ST3GAL1和ST3GAL2以及相应的α-2,3-连接唾液酸在黑色素瘤中上调，并且对黑色素瘤生长至关重要。糖蛋白质组学显示，ST3GAL1和ST3GAL2的糖蛋白靶点富含参与生长信号传导的跨膜蛋白，包括氨基酸转运体SLC3A2/CD98hc。抑制CD98hc模拟了ST3GAL1和ST3GAL2沉默的效果，抑制了黑色素瘤细胞的增殖。我们发现，CD98hc的蛋白质稳定性及其对黑色素瘤的促生存作用均依赖于ST3GAL1和ST3GAL2介导的α-2,3-唾液酸化。我们的研究揭示了α-2,3-唾液酸在功能上有助于黑色素瘤的维持，支持将ST3GAL1和ST3GAL2作为黑色素瘤的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/b9ae49e1e65b/sciadv.adg3481-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/1f06d5309790/sciadv.adg3481-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/a9a6d7e0f6f4/sciadv.adg3481-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/8335eb0b4890/sciadv.adg3481-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/1c00e13a996a/sciadv.adg3481-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/c8bb36e7d742/sciadv.adg3481-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/b9ae49e1e65b/sciadv.adg3481-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/1f06d5309790/sciadv.adg3481-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/a9a6d7e0f6f4/sciadv.adg3481-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/8335eb0b4890/sciadv.adg3481-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/1c00e13a996a/sciadv.adg3481-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/c8bb36e7d742/sciadv.adg3481-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c4/12227053/b9ae49e1e65b/sciadv.adg3481-f6.jpg

相似文献

[1]
Integrated in vivo functional screens and multiomics analyses identify α-2,3-sialylation as essential for melanoma maintenance.

Sci Adv. 2025-7-4

[2]
Integrated functional screens and multi-omics analyses identify α-2,3-sialylation as essential for melanoma maintenance.

bioRxiv. 2024-3-12

[3]
Screening the human miRNA interactome reveals coordinated up-regulation in melanoma, adding bidirectional regulation to miRNA networks.

Sci Adv. 2025-1-10

[4]
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[5]
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Blood Adv. 2022-7-12

[6]
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Cancer Res Commun. 2025-7-1

[7]
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Glycobiology. 2025-6-23

[8]
EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update.

Eur J Cancer. 2007-1

[9]
Incidence, stage and outcome of malignant melanoma, keratinocyte and other cancers in individuals with vitiligo or alopecia: intraindividual or familial risks?

Br J Dermatol. 2025-6-20

[10]
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J Transl Med. 2025-7-2

本文引用的文献

[1]
A cellular hierarchy in melanoma uncouples growth and metastasis.

Nature. 2022-10

[2]
N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98).

Sci Rep. 2022-8-26

[3]
Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes.

Nature. 2022-5

[4]
Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses.

Blood Adv. 2022-6-14

[5]
Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis.

Cancer Discov. 2022-5-2

[6]
A Useful Guide to Lectin Binding: Machine-Learning Directed Annotation of 57 Unique Lectin Specificities.

ACS Chem Biol. 2022-11-18

[7]
Role of galectin 3 binding protein in cancer progression: a potential novel therapeutic target.

J Transl Med. 2021-9-26

[8]
The Role of Glycosylation in Melanoma Progression.

Cells. 2021-8-19

[9]
SLC1A4: A Powerful Prognostic Marker and Promising Therapeutic Target for HCC.

Front Oncol. 2021-3-11

[10]
Biophysical characterization of melanoma cell phenotype markers during metastatic progression.

Eur Biophys J. 2021-5

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