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

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...

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Autores principales: Wang, Jun, Liu, Gao, Liu, Mei, Cai, Qinzhen, Yao, Cong, Chen, Hao, Song, Neng, Yuan, Chunhui, Tan, Decai, Hu, Yuhai, Xiang, Yun, Xiang, Tian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564291/
https://www.ncbi.nlm.nih.gov/pubmed/34745942
http://dx.doi.org/10.3389/fonc.2021.716246
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author Wang, Jun
Liu, Gao
Liu, Mei
Cai, Qinzhen
Yao, Cong
Chen, Hao
Song, Neng
Yuan, Chunhui
Tan, Decai
Hu, Yuhai
Xiang, Yun
Xiang, Tian
author_facet Wang, Jun
Liu, Gao
Liu, Mei
Cai, Qinzhen
Yao, Cong
Chen, Hao
Song, Neng
Yuan, Chunhui
Tan, Decai
Hu, Yuhai
Xiang, Yun
Xiang, Tian
author_sort Wang, Jun
collection PubMed
description 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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spelling pubmed-85642912021-11-04 High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells Wang, Jun Liu, Gao Liu, Mei Cai, Qinzhen Yao, Cong Chen, Hao Song, Neng Yuan, Chunhui Tan, Decai Hu, Yuhai Xiang, Yun Xiang, Tian Front Oncol Oncology 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. Frontiers Media S.A. 2021-10-20 /pmc/articles/PMC8564291/ /pubmed/34745942 http://dx.doi.org/10.3389/fonc.2021.716246 Text en Copyright © 2021 Wang, Liu, Liu, Cai, Yao, Chen, Song, Yuan, Tan, Hu, Xiang and Xiang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Wang, Jun
Liu, Gao
Liu, Mei
Cai, Qinzhen
Yao, Cong
Chen, Hao
Song, Neng
Yuan, Chunhui
Tan, Decai
Hu, Yuhai
Xiang, Yun
Xiang, Tian
High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells
title High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells
title_full High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells
title_fullStr High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells
title_full_unstemmed High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells
title_short High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells
title_sort high-risk hpv16 e6 activates the cgmp/pkg pathway through glycosyltransferase st6gal1 in cervical cancer cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564291/
https://www.ncbi.nlm.nih.gov/pubmed/34745942
http://dx.doi.org/10.3389/fonc.2021.716246
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