Galactosyltransferase B4GALT1 confers chemoresistance in pancreatic ductal adenocarcinomas by upregulating N-linked glycosylation of CDK11p110

Chen, Yitian; Su, Lili; Huang, Cheng; Wu, Sangqing; Qiu, Xiaoyi; Zhao, Xu; Meng, Qiong; Meng, Ya-Ming; Kong, Xiangbin; Wang, Minghui; Liu, Chao; Wong, Ping-Pui

doi:10.1016/j.canlet.2020.12.006

Cited by 23 publications

(19 citation statements)

References 37 publications

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“…Interestingly, we found two putative p65 binding motif on METTL14 promoter region after analyzing the promoter sequence of METTL14. Consistent with other’s report ( 42 ), we found phosphorylation level of p65 was increased in our gemcitabine resistant cell lines. Inhibition of METTL14 by siRNA knockdown significantly decreased the expression level of METTL14, while overexpressing p65 increased METTL14 expression.…”

Section: Discussionsupporting

confidence: 93%

“…Although the expression of METTL14 was increased in the resistant pancreatic cancer cells, the regulatory mechanism of expression remains unclear. Transcriptional factor p65 has been reported to link to gemcitabine resistance, and elevated p65 activity was found in gemcitabine resistant pancreatic cancer cell line-MIA Paca2 ( 41 , 42 ). Thus, we wonder whether p65 could regulate the expression of METTL14.…”

Section: Discussionmentioning

confidence: 99%

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m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer

Zhang

Zhou

et al. 2021

Front. Oncol.

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ObjectivePancreatic cancer is one of the most lethal human malignancies. Gemcitabine is widely used to treat pancreatic cancer, and the resistance to chemotherapy is the major difficulty in treating the disease. N6-methyladenosine (m6A) modification, which regulates RNA splicing, stability, translocation, and translation, plays critical roles in cancer physiological and pathological processes. METTL14, an m6A Lmethyltransferase, was found deregulated in multiple cancer types. However, its role in gemcitabine resistance in pancreatic cancer remains elusive.MethodsThe mRNA and protein level of m6A modification associated genes were assessed by QRT-PCR and western blotting. Then, gemcitabine‐resistant pancreatic cancer cells were established. The growth of pancreatic cancer cells were analyzed using CCK8 assay and colony formation assay. METTL14 was depleted by using shRNA. The binding of p65 on METTL14 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Protein level of deoxycytidine kinase (DCK) and cytidine deaminase (CDA) was evaluated by western blotting. In vivo experiments were conducted to further confirm the critical role of METTL14 in gemcitabine resistance.ResultsWe found that gemcitabine treatment significantly increased the expression of m6A methyltransferase METTL14, and METTL14 was up-regulated in gemcitabine-resistance human pancreatic cancer cells. Suppression of METTL14 obviously increased the sensitivity of gemcitabine in resistant cells. Moreover, we identified that transcriptional factor p65 targeted the promoter region of METTL14 and up-regulated its expression, which then increased the expression of cytidine deaminase (CDA), an enzyme inactivates gemcitabine. Furthermore, in vivo experiment showed that depletion of METTL14 rescue the response of resistance cell to gemcitabine in a xenograft model.ConclusionOur study suggested that METTL14 is a potential target for chemotherapy resistance in pancreatic cancer.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer

Zhang

Zhou

et al. 2021

Front. Oncol.

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“…Increased expression of B4GALNT1 promotes metastasis of lung adenocarcinoma and melanoma ( 43 , 44 ). B4GALT1 upregulates glycosylation of CDK11 p110 and therefore confers chemoresistance of pancreatic ductal adenocarcinomas ( 45 ). Although poly-N-acetyllactosamine and its corresponding glycotransferases (B3GNT2 and B3GNT3) that facilitate PD-L1/PD-1 stabilization and interaction ( 19 – 21 ) showed no changes in response to exogenous E6 expression, the enhanced MAN2A1 expression has been reported to result in the dysfunction of T cells in tumor microenvironment, and its inhibition enhances the immune response to anti-PD-L1 in human tumors ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells

Wang

Liu

et al. 2021

Front. Oncol.

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Alterations in glycosylation regulate fundamental molecular and cellular processes of cancer, serving as important biomarkers and therapeutic targets. However, the potential association and regulatory mechanisms of E6 oncoprotein on glycosylation of cervical cancer cells are still unclear. Here, we evaluated the glycomic changes via using Lectin microarray and determined the corresponding enzymes associated with endogenous high-risk HPV16 E6 expression in cervical cancer cells. α-2,6 sialic acids and the corresponding glycosyltransferase ST6GAL1 were significantly increased in E6 stable-expressing HPV− cervical cancer C33A cells. Clinical validation further showed that the expression of ST6GAL1 was significantly increased in patients infected with high-risk HPV subtypes and showed a positive association with E6 in cervical scraping samples. Interfering ST6GAL1 expression markedly blocked the oncogenic effects of E6 on colony formulation, proliferation, and metastasis. Importantly, ST6GAL1 overexpression enhanced tumorigenic activities of both E6-positive and E6-negative cells. Mechanistical investigations revealed that E6 depended on activating YAP1 to stimulate ST6GAL1 expression, as verteporfin (inhibitor of YAP1) significantly suppressed the E6-induced ST6GAL1 upregulation. E6/ST6GAL1 triggered the activation of downstream cGMP/PKG signaling pathway and ODQ (inhibitor of GMP production) simultaneously suppressed the oncogenic activities of both E6 and ST6GAL1 in cervical cancer cells. Taken together, these findings indicate that ST6GAL1 is an important mediator for oncogenic E6 protein to activate the downstream cGMP/PKG signaling pathway, which represents a novel molecular mechanism and potential therapeutic targets for cervical cancer.

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“…In PDOs obtained over multiple years in a metastatic PDAC patient, it was possible to show increased organoid resistance to chemotherapy in accord with treatment refractory cases ( Tiriac et al, 2018 ). Organoid work has also shown that Beta-1,4-galactosyltransferase 1 (B4GALT1) promotes PDAC progression and chemoresistance via stabilization of CDK11 p 110 ( Chen et al, 2021 , 110). In the biomarker field, organoids showed that higher EV release is coupled to a high cell proliferation rate, promoted by Wnt pathway activation ( Sándor et al, 2021 ).…”

Section: In Vitro Preclinical Modelsmentioning

confidence: 99%

Pre-clinical Models of Metastasis in Pancreatic Cancer

Miquel

Zhang

Pilarsky

2021

Front. Cell Dev. Biol.

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Pancreatic ductal adenocarcinoma (PDAC) is a hostile solid malignancy coupled with an extremely high mortality rate. Metastatic disease is already found in most patients at the time of diagnosis, resulting in a 5-year survival rate below 5%. Improved comprehension of the mechanisms leading to metastasis is pivotal for the development of new targeted therapies. A key field to be improved are modeling strategies applied in assessing cancer progression, since traditional platforms fail in recapitulating the complexity of PDAC. Consequently, there is a compelling demand for new preclinical models that mirror tumor progression incorporating the pressure of the immune system, tumor microenvironment, as well as molecular aspects of PDAC. We suggest the incorporation of 3D organoids derived from genetically engineered mouse models or patients as promising new tools capable to transform PDAC pre-clinical modeling and access new frontiers in personalized medicine.

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Galactosyltransferase B4GALT1 confers chemoresistance in pancreatic ductal adenocarcinomas by upregulating N-linked glycosylation of CDK11p110

Cited by 23 publications

References 37 publications

m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer

m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer

High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells

Pre-clinical Models of Metastasis in Pancreatic Cancer

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