Sialyltransferase inhibition and recent advances

Wang, Libo; Liu, Ying; Wu, Lijun; Sun, Xue‐Long

doi:10.1016/j.bbapap.2015.07.007

Cited by 82 publications

(58 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Next, we determined whether compounds that alter N-glycan processing could promote EHT and HSPC overexpansion, similar to loss of miR-223. Briefly, we treated wild-type embryos undergoing EHT with swainsonine (SW) to enhance mannose-biased modification 37 , or a pan-sialyltransferase inhibitor (ST) to diminish terminal sialic acid incorporation 40 (Fig. 4 f-j and Supplementary Fig.…”

Section: Figurementioning

confidence: 99%

The N-Glycome regulates the endothelial-to-hematopoietic transition

Kasper

Hintzen

et al. 2019

Preprint

View full text Add to dashboard Cite

20Hematopoietic stem and progenitor cells (HSPCs) are required to establish and maintain the 21 adult blood system in vertebrates. During development, hemogenic endothelial cells undergo an 22 endothelial-to-hematopoietic transition (EHT) to generate HSPCs 1-4 . Growth factors and 23 epigenetic changes can promote EHT 1,3,5 , but these mechanisms do not explain its tight 24 spatiotemporal regulation during development. Here, we show that microRNA (miR) miR-223-25 mediated regulation of N-glycan biosynthesis intrinsically restrains EHT, representing the first 26 pathway that prevents excessive HSPC production. We find that miR-223 is uniquely expressed 27 in hemogenic endothelial cells undergoing EHT and in nascent HSPCs. Loss of miR-223 28 promotes the expansion of these cells in the zebrafish and mouse aorta-gonad-mesonephros 29 (AGM), where EHT occurs 6-8 . miR-223 targets alg2 (α1,3/ α1,6 mannosyltransferase) and 30 st3gal2 (α2,3 sialyltransferase) for repression in the AGM endothelium. These two enzymes are 31 involved in the biosynthesis of N-glycans, a common co-translational modification 9,10 that 32 influences several pathophysiological processes 11,12 , but has not yet been implicated in EHT. 33 Using an N-glycosensor, we demonstrate that vascular N-glycosylation increases during EHT, 34 and this process is disrupted upon loss of miR-223. Specifically, high-throughput glycome 35 analysis revealed terminal α1,3 mannose and α2,3 sialic acid modifications of membrane 36 proteins are altered upon loss of miR-223. Importantly, pharmacological manipulation targeting 37 these N-glycan types in wild-type embryos phenocopies the loss of miR-223 and enhances EHT 38 as well as HSPC production. Thus, the N-glycome plays a previously unappreciated role as an 39 intrinsic negative regulator of EHT, with specific mannose and sialic acid modifications serving 40as key endothelial determinants of the hematopoietic fate. 41 43Zebrafish endothelial-to-hematopoietic transition (EHT) has emerged as an instrumental 44 model to understand the formation and regulation of definitive hematopoietic stem and 45 progenitor cells (HSPCs) with long-term engraftment capability. As in their mammalian 46 counterparts, EHT occurs in endothelial cells that co-express vascular and hematopoietic genes 47

show abstract

Section: Figurementioning

confidence: 99%

The N-Glycome regulates the endothelial-to-hematopoietic transition

Kasper

Hintzen

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous reports demonstrated that sialic acid is involved in various biological processes, including cell-cell adhesion, immune defence, tumour cell metastasis, and inflammation [7–10]. Increasing evidence has indicated that the ST8SIA family is associated with several human tumours.…”

Section: Introductionmentioning

confidence: 99%

miR-146a and miR-146b promote proliferation, migration and invasion of follicular thyroid carcinoma via inhibition of ST8SIA4

Zhao

Liang

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Follicular thyroid carcinoma (FTC) is a more aggressive form of thyroid cancer than the common papillary type. Alpha-2,8-sialyltransferase (ST8SIA) family members are expressed in various cancers and may be associated with FTC progression. In this study, we measured ST8SIA family expression in two FTC cell lines with different invasive potentials (FTC-133 and FTC-238) and Nthy-ori 3-1 cell lines, as well as FTC and normal thyroid tissues. ST8SIA4 was downregulated in the highly invasive FTC-238 cells and FTC tissues. Additionally, ST8SIA4 inhibited proliferation, migration and invasion of FTC both in vitro and in vivo. miR-146a and miR-146b were previously shown to be upregulated in thyroid carcinoma, and bioinformatics analyses indicated that miR-146a and miR-146b inhibit ST8SIA4. We found that miR-146a and miR-146b were significantly upregulated in FTC and promoted tumour progression. Furthermore, ST8SIA4 restoration decreased the invasiveness of miR-146a/b-overexpressing FTC-133 cells, and ST8SIA4 suppression reversed the effects of miR-146a/b inhibition in FTC-238 cells. We showed that miR-146a/b activated the PI3K-AKT-mTOR signalling pathway at least partially via suppression of ST8SIA4. Thus, our results demonstrate that miR-146a and miR-146b promote proliferation, migration and invasion of FTC via inhibition of ST8SIA4.

show abstract

“…Because hypersialylation in malignant cells has been shown to be a mechanism of immune evasion [59][60][61] , preclinical studies focusing on depleting tumor sialylation have developed several promising therapeutic strategies 62 . One such example is the fluorinated sialic acid analogue we used in our study, 3F-NeuAc.…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of regulators of antibody-drug conjugate toxicity using CRISPR-Cas9 screens

et al. 2019

Preprint

View full text Add to dashboard Cite

Antibody-drug conjugates (ADCs) selectively deliver highly toxic chemotherapeutic agents to target antigen-expressing cells and have become an important cancer treatment in recent years.However, the molecular mechanisms by which ADCs are internalized and activated within cells remain unclear. Here we use CRISPR-Cas9 screens to identify genes that control the toxicity of ADCs. Our results demonstrate critical roles for a range of known and novel endolysosomal trafficking regulators in ADC toxicity. We identify and characterize C18orf8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation. Through comparative analysis of CRISPR screens with ADCs bearing a noncleavable linker versus a cleavable valine-citrulline (VC) linker, we show that a subset of late endosomal and lysosomal regulators are selectively essential for toxicity of noncleavable linker ADCs. We further show that cleavable VC linkers are rapidly processed upon internalization and therefore surprisingly appear to bypass the requirement of lysosomal delivery. Lastly, we show that inhibition of sialic acid biosynthesis sensitizes cells to ADC treatment by increasing the rate of ADC internalization. This sensitization was observed using several ADCs targeting different antigens in diverse cancer cell types, including the FDA-approved ADC trastuzumab emtansine (T-DM1) in Her2-positive breast cancer cells. Together, these results reveal novel regulators of endolysosomal trafficking, provide important insights to guide future ADC design, and identify candidate combination therapy targets as well as potential mechanisms of ADC resistance.

show abstract

Sialyltransferase inhibition and recent advances

Cited by 82 publications

References 49 publications

The N-Glycome regulates the endothelial-to-hematopoietic transition

The N-Glycome regulates the endothelial-to-hematopoietic transition

miR-146a and miR-146b promote proliferation, migration and invasion of follicular thyroid carcinoma via inhibition of ST8SIA4

Systematic identification of regulators of antibody-drug conjugate toxicity using CRISPR-Cas9 screens

Contact Info

Product

Resources

About