NEU4 inhibits motility of HCC cells by cleaving sialic acids on CD44

Zhang, Xiaoqing; Dou, Peng; Akhtar, Muhammad; Liu, Fei; Hu, Xibo; Yang, Lijun; Yang, Depeng; Zhang, Xiaohan; Li, Yiqun; Qiao, Shupei; Li, Kai; Tang, Ran; Zhan, Cheng; Ma, Yue; Cheng, Qixiang; Bai, Yan; Han, Fangfang; Nie, Huan; Yu, Li

doi:10.1038/s41388-021-01955-7

Cited by 21 publications

(18 citation statements)

References 51 publications

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“…Sialylation has long been described as a driver of cancer cells invasion, namely through the promotion of less cohesive cell phenotypes due to repulsive effects between proteins at the cell surface (83,84). In fact, some reports suggest that sialylation could decrease the interaction of CD44 with its ligand hyaluronic acid, whose interaction contributes to cancer invasiveness and metastasis (25).…”

Section: Discussionmentioning

confidence: 99%

“…In the past, we and other groups have demonstrated how glycosylation may increase the cancer specificity of proteins, which could be explored for precise cancer-targeting (25,(37)(38)(39)(40)(41). CD44 presents multiple potential O-glycosylation sites in its extracellular domain, mostly in the variable region, which could be explored towards this objective (2).…”

Section: Bc Expresses Cd44 Glycoproteoforms Not Observed In Relevant Healthy Cells/organsmentioning

confidence: 99%

“…Moreover, a multiplicity of different but closely related glycan structures may be found in the same protein, exponentiating molecular micro-, macro-, and meta-heterogeneity (2,24). Still, few studies have addressed the CD44 glycocode in cancer and its functional implications for disease progression (25)(26)(27). Moreover, conflicting results have been generated concerning its role in disease and clinical value, which are directly linked to analytical limitations for unequivocal molecular characterization, mostly due to the lack of high-throughput approaches to characterize CD44 at the protein level (2).…”

Section: Introductionmentioning

confidence: 99%

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Glycoproteogenomics characterizes the CD44 splicing code driving bladder cancer invasion

Gaiteiro

Soares

Santos

et al. 2021

Preprint

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Bladder cancer (BC) management demands the introduction of novel molecular targets for precision medicine. Cell surface glycoprotein CD44 has been widely studied as a potential biomarker of BC aggressiveness and cancer stem cells. However, significant alternative splicing and multiple glycosylation generate a myriad of glycoproteoforms with potentially distinct functional roles. The lack of tools for precise molecular characterization has led to conflicting results, delaying clinical applications. Addressing these limitations, we have interrogated the transcriptome of a large BC patient cohort for splicing signatures. Remarkable CD44 heterogeneity was observed, as well as associations between short CD44 standard splicing isoform (CD44s), invasion and poor prognosis. In parallel, immunoassays showed that targeting short O-glycoforms could hold the key to improve CD44 cancer specificity. This prompted the development of a glycoproteogenomics approach, building on the integration of transcriptomics-customized datasets and glycomics for protein annotation from nanoLC-ESI-MS/MS experiments. The concept was applied to invasive human BC cell lines, glycoengineered cells, and tumor tissues, enabling unequivocal CD44s identification. Finally, we confirmed the link between CD44s and invasion in vitro by siRNA knockdown, supporting findings from BC tissues. The key role played by short-chain O-glycans in CD44-mediated invasion was also demonstrated through glycoengineered cell models. Overall, CD44s emerged as biomarker of poor prognosis and CD44-Tn/STn as promising molecular signatures for targeted interventions. This study materializes the concept of glycoproteogenomics and provides a key vision to address the cancer splicing code at the protein level, which may now be expanded to better understand CD44 functional role in health and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Bc Expresses Cd44 Glycoproteoforms Not Observed In Relevant Healthy Cells/organsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glycoproteogenomics characterizes the CD44 splicing code driving bladder cancer invasion

Gaiteiro

Soares

Santos

et al. 2021

Preprint

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“…In the past, we and other groups have demonstrated how glycosylation may increase the cancer specificity of proteins, which could be explored for precise cancer-targeting 25 , 31 , 32 , 34 , 47 , 48 . CD44 presents multiple potential O -glycosylation sites in its extracellular domain, mostly in the variable region, which could be explored towards this objective 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, a multiplicity of different but closely related glycan structures may be found in the same protein, exponentiating molecular micro-, macro-, and meta-heterogeneity 2 , 24 . Still, few studies have addressed the CD44 glycocode in cancer and its functional implications for disease progression 25 - 27 . Moreover, conflicting results have been generated concerning its role in disease and clinical value, which are directly linked to analytical limitations for unequivocal molecular characterization, mostly due to the lack of high-throughput approaches to characterize CD44 at the protein level 2 .…”

Section: Introductionmentioning

confidence: 99%

Glycoproteogenomics characterizes the CD44 splicing code associated with bladder cancer invasion

Gaiteiro¹,

Soares²,

Relvas-Santos³

et al. 2022

Theranostics

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Rationale: Bladder cancer (BC) management demands the introduction of novel molecular targets for precision medicine. Cell surface glycoprotein CD44 has been widely studied as a potential biomarker of BC aggressiveness and cancer stem cells. However, significant alternative splicing and multiple glycosylation generate a myriad of glycoproteoforms with potentially distinct functional roles. The lack of tools for precise molecular characterization has led to conflicting results, delaying clinical applications. Addressing these limitations, we have interrogated the transcriptome and glycoproteome of a large BC patient cohort for splicing signatures. Methods: CD44 gene and its splicing variants were assessed by Real Time-Polymerase Chain Reaction (RT-PCR) and RNAseq in tumor tissues. The co-localization of CD44 and short O -glycans was evaluated by proximity ligation assay (PLA), immunohistochemistry and double-immunofluorescence. An innovative glycoproteogenomics approach, integrating transcriptomics-customized datasets and glycomics for protein annotation from nanoLC-ESI-MS/MS experiments, was developed and implemented to identify CD44 variants and associated glycosignatures. The impact of CD44 silencing on proliferation and invasion of BC cell lines and glycoengineered cells was determined by BrdU ELISA and Matrigel invasion assays, respectively. Antibody phosphoarrays were used to investigate the role of CD44 and its glycoforms in the activation of relevant oncogenic signaling pathways. Results: Transcriptomics analysis revealed remarkable CD44 isoforms heterogeneity in bladder cancer tissues, as well as associations between short CD44 standard splicing isoform (CD44s), invasion and poor prognosis. We further demonstrated that targeting short O -glycoforms such as the Tn and sialyl-Tn antigens was key to overcome the lack of cancer specificity presented by CD44. Glycoproteogenomics allowed, for the first time, the comprehensive characterization of CD44 splicing code at the protein level. The concept was applied to invasive human BC cell lines, glycoengineered cells, and tumor tissues, enabling unequivocal CD44s identification as well as associated glycoforms. Finally, we confirmed the link between CD44 and invasion in CD44s-enriched cells in vitro by small interfering RNA (siRNA) knockdown, supporting findings from BC tissues. The key role played by short-chain O -glycans in CD44-mediated invasion was also demonstrated through glycoengineered cell models. Conclusions: Overall, CD44s emerged as biomarker of poor prognosis and CD44-Tn/ Sialyl-Tn (STn) as promising molecular signatures for targeted interventions. This study materializes the concept of glycoproteogenomics and provides a key vision to address the cancer splicing code at the protein level, which may now be expanded to better understand CD44 functional role in ...

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Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice

Xiao,

Hao,

Kuang

et al. 2024

Advanced Science

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Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial‐to‐mesenchymal transition, reduces the production of pro‐fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254‐388aa interacts with Yes‐associated protein (YAP) at WW2 domain (231‐263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3ʹ,4ʹ‐Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4‐dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.

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NEU4 inhibits motility of HCC cells by cleaving sialic acids on CD44

Cited by 21 publications

References 51 publications

Glycoproteogenomics characterizes the CD44 splicing code driving bladder cancer invasion

Glycoproteogenomics characterizes the CD44 splicing code driving bladder cancer invasion

Glycoproteogenomics characterizes the CD44 splicing code associated with bladder cancer invasion

Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice

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