ST6GalNAc‐I promotes lung cancer metastasis by altering MUC5AC sialylation

Lakshmanan, Imayavaramban; Chaudhary, Sanjib; Vengoji, Raghupathy; Seshacharyulu, Parthasarathy; Carmicheal, Joseph; Jahan, Rahat; Atri, Pranita; Chirravuri-Venkata, Ramakanth; Gupta, Rohitesh; Marimuthu, Saravanakumar; Perumal, Naveenkumar; Kaur, Sukhwinder; Mallya, Kavita; Smith, Lynette M.; Lele, Subodh M.; Ponnusamy, Moorthy P.; Nasser, Mohd W.; Salgia, Ravi; Batra, Surinder K.; Ganti, Apar Kishor

doi:10.1002/1878-0261.12956

Cited by 22 publications

(16 citation statements)

References 50 publications

(91 reference statements)

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“…However, a significant increase of hSTGalNAc I gene expression by curcumin was not observed in A549, U-87 MG and MCF-7 cells, indicating a cell typespecific hSTGalNAc I gene expression by curcumin. Similarly, previous studies showed that most breast cancer cell lines, such as MCF-7, MDA-MB-231 and T47D (Julien et al, 2001(Julien et al, , 2006Sewell et al, 2006), and lung cancer cell line, including A549 (Lakshmanan et al, 2021), do not express hST6GalNAc I mRNA transcript or sTn antigen.…”

Section: Discussionsupporting

confidence: 60%

Curcumin-mediated transcriptional regulation of human N-acetylgalactosamine-α2,6-sialyltransferase which synthesizes sialyl-Tn antigen in HCT116 human colon cancer cells

Kim

Cho

et al. 2022

Front. Mol. Biosci.

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Human N-acetylgalactosamine-α2,6-sialyltransferase (hST6GalNAc I) is the major enzyme involved in the biosynthesis of sialyl-Tn antigen (sTn), which is known to be expressed in more than 80% of human carcinomas and correlated with poor prognosis in cancer patients. Athough high expression of hST6GalNAc I is associated with augmented proliferation, migration and invasion in various cancer cells, transcriptional mechanism regulating hST6GalNAc I gene expression remains largely unknown. In this study, we found that hST6GalNAc I gene expression was markedly augmented by curcumin in HCT116 human colon carcinoma cells. To understand the molecular mechanism for the upregulation of hST6GalNAc I gene expression by curcumin in HCT116 cells, we first determined the transcriptional start site of hST6GalNAc I gene by 5′-RACE and cloned the proximal hST6GalNAc I 5′-flanking region spanning about 2 kb by PCR. Functional analysis of the hST6GalNAc I 5′ flanking region of hST6GalNAc I by sequential 5′-deletion, transient transfection of reporter gene constructs and luciferase reporter assays showed that -378/-136 region is essential for maximal activation of transcription in response to curcumin in HCT 116 cells. This region includes putative binding sites for transcription factors c-Ets-1, NF-1, GATA-1, ER-α, YY1, and GR-α. ChIP analysis and site-directed mutagenesis demonstrated that estrogen receptor α (ER-α) binding site (nucleotides -248/-238) in this region is crucial for hST6GalNAc I gene transcription in response to curcumin stimulation in HCT116 cells. The transcription activity of hST6GalNAc I gene induced by curcumin in HCT116 cells was strongly inhibited by PKC inhibitor (Gö6983) and ERK inhibitor (U0126). These results suggest that curcumin-induced hST6GalNAc I gene expression in HCT116 cells is modulated through PKC/ERKs signal pathway.

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Section: Discussionsupporting

confidence: 60%

Curcumin-mediated transcriptional regulation of human N-acetylgalactosamine-α2,6-sialyltransferase which synthesizes sialyl-Tn antigen in HCT116 human colon cancer cells

Kim

Cho

et al. 2022

Front. Mol. Biosci.

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“…Dysregulated MUC5AC expression and its oncogenic role have been documented in malignant conditions, including colon, pancreatic and lung cancers. [20][21][22] It has been shown that during the progression from atypical lung adenomatous hyperplasia to adenocarcinoma, MUC5AC expression gradually increases, suggesting that MUC5AC may promote the development of lung adenocarcinoma. 17 In the present study, higher MUC5AC expression was found in lung ADC tissue than in adjacent normal lung tissue and correlated with worse disease-free survival and overall survival.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulated MUC5AC expression and its oncogenic role have been documented in malignant conditions, including colon, pancreatic and lung cancers 20–22 . It has been shown that during the progression from atypical lung adenomatous hyperplasia to adenocarcinoma, MUC5AC expression gradually increases, suggesting that MUC5AC may promote the development of lung adenocarcinoma 17 .…”

Section: Discussionmentioning

confidence: 99%

Molecular insight of p53/Sp1/MUC5AC axis in the tumorigenesis and progression of lung adenocarcinoma

Zhang

et al. 2022

Clin Exp Pharma Physio

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The aberrant expression of secretory mucin MUC5AC has been documented during the tumourigenesis and progression of various cancers. However, little is currently known on the function of MUC5AC in lung adenocarcinoma. The present study focused on the tumour‐promoting role of MUC5AC and its regulatory mechanisms in lung adenocarcinoma. Firstly, MUC5AC expression was evaluated in NSCLC tissue microarrays by immunohistochemistry. Kaplan–Meier analysis were used to clarify the prognostic value of MUC5AC. Subsequently, small interfering RNA and small hairpin RNA were used to knockdown MUC5AC in lung ADC cell lines to elucidate its role in tumorigenesis and progression of lung adenocarcinoma via in vitro functional assays and xenograft mouse models. Finally, the regulatory mechanisms underlying p53/Sp1/MUC5AC axis were identified through dual‐luciferase report. We found that MUC5AC was upregulated in lung ADC tissues and cell lines, especially in KRAS‐mutant cases and correlated with poor prognosis. MUC5AC gene silencing resulted in reduced cell proliferation, invasion and migration. Furthermore, knockdown of MUC5AC led to reversion of the epithelial–mesenchymal transition. Additionally, downregulation of MUC5AC reduced tumourigenesis in mouse models. Finally, we found an antagonistic role between Sp1 and p53 in the regulation of MUC5AC gene expression. Our findings suggest that high MUC5AC expression promotes tumourigenesis and progression of lung ADC. Both p53 gene inactivation and Sp1 overexpression in lung ADC may enhance MUC5AC expression, especially in KRAS‐mutated cases. Given the paucity of efficient drug‐targeted approaches of KRAS‐driven lung ADCs, therapies directed at downstream effectors such as MUC5AC could have huge prospects.

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“…ST6GalNAc‐I is an O‐glycosyltransferase that catalyzes the addition of sialic acid to the initiating GalNAc residues forming sialyl Tn (STn) on glycoproteins. In lung cancer, Lakshmanan et al 10 . demonstrated that mutant p53 R175H mediates ST6GalNAc‐I expression, leading to the sialyation of MUC5AC.…”

Section: Figurementioning

confidence: 99%

“…9 ST6GalNAc-I is an O-glycosyltransferase that catalyzes the addition of sialic acid to the initiating GalNAc residues forming sialyl Tn (STn) on glycoproteins. In lung cancer, Lakshmanan et al 10 demonstrated that mutant p53 R175H mediates ST6GalNAc-I expression, leading to the sialyation of MUC5AC. GALNT3, GALNT5 and B3GNT3 GTs mRNA expression were downregulated in ST6GalNAc-I KO cells, whereas FUT9, COLGALT2, HAS3 and ST8Sia2 were upregulated in lung cancer cells.…”

mentioning

confidence: 99%

Pan‐cancer analysis of altered glycosyltransferases confers poor clinical outcomes

Marimuthu

Batra

Ponnusamy

2022

Clinical and Translational Dis

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Glycosylation is a post-translational modification (PTM) process that attaches carbohydrates to proteins and lipids. Protein glycosylation can be N-linked or O-linked depending on adding sugars onto the side chains of Asn or Ser/Thr residues, respectively. PTM comprises glycan-modifying enzymes glycosyltransferases (GTs) and glycosidases. Oglycan truncation, N-glycan branching, sialylation and fucosylation are the most well-known cancer-associated glycosylations. The glycan-modifying enzymes stimulate various malignant behaviours of tumours, such as tumour proliferation, invasion, epithelial-mesenchymal transition, metastasis, angiogenesis, immune modulation and cellmatrix interactions. 1,2 Over 200 GTs regulate glycosylation. An unbiased global approach must be used to identify glycogenes in cancer. In this study, Li et al. 3 (2022) investigated the fascinating examination of GTs in pan-cancer using bioinformatics investigation from CCLE, TCGA,This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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ST6GalNAc‐I promotes lung cancer metastasis by altering MUC5AC sialylation

Abstract: mutant p53 R175H mediates ST6GalNAc-I expression, leading to the sialyation of MUC5AC, and thus contribute to LC liver metastasis.

Cited by 22 publications

References 50 publications

Curcumin-mediated transcriptional regulation of human N-acetylgalactosamine-α2,6-sialyltransferase which synthesizes sialyl-Tn antigen in HCT116 human colon cancer cells

Curcumin-mediated transcriptional regulation of human N-acetylgalactosamine-α2,6-sialyltransferase which synthesizes sialyl-Tn antigen in HCT116 human colon cancer cells

Molecular insight of p53/Sp1/MUC5AC axis in the tumorigenesis and progression of lung adenocarcinoma

Pan‐cancer analysis of altered glycosyltransferases confers poor clinical outcomes

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