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

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-04 DOI:10.1126/sciadv.adg3481

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

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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.

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综合体内功能筛选和多组学分析确定α-2,3-唾液酰化对黑色素瘤维持至关重要

异常糖基化是癌症生物学的一个标志，糖基化改变影响黑色素瘤进展的多个方面。为了鉴定黑色素瘤维持所必需的糖基转移酶、聚糖和糖蛋白，我们利用糖基转移酶的短发夹RNA库、良性痣和黑色素瘤样本的凝集素微阵列分析和基于质谱的糖蛋白组学进行了体内生长筛选。我们发现α-2,3-唾液基转移酶ST3GAL1和ST3GAL2以及相应的α-2,3-连接唾液苷在黑色素瘤中与痣相比上调，并且对黑色素瘤的生长至关重要。糖蛋白组学发现，ST3GAL1和ST3GAL2的糖蛋白靶点在参与生长信号传导的跨膜蛋白中富集，包括氨基酸转运体SLC3A2/CD98hc。CD98hc抑制模拟ST3GAL1和ST3GAL2沉默的效果，抑制黑色素瘤细胞增殖。我们发现CD98hc蛋白的稳定性及其对黑色素瘤的促生存作用都依赖于ST3GAL1和ST3GAL2介导的α-2,3-唾液酰化。我们的研究显示α-2,3-唾液皂苷对黑色素瘤的维持有功能贡献，支持ST3GAL1和ST3GAL2作为黑色素瘤的治疗靶点。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.