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HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis

Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. HTLV-1 exerts its oncogenic functions by interacting with signaling pathways involved in cell proliferation and transformation. Dysregulation of the Hippo/YAP pathway is...

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Autores principales: Zhao, Tiejun, Wang, Zhilong, Fang, Jinyong, Cheng, Wenzhao, Zhang, Yiling, Huang, Jinhua, Xu, Lingling, Gou, Hongwei, Zeng, Linghui, Jin, Zhigang, Matsuoka, Masao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892356/
https://www.ncbi.nlm.nih.gov/pubmed/35210364
http://dx.doi.org/10.1073/pnas.2115316119
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author Zhao, Tiejun
Wang, Zhilong
Fang, Jinyong
Cheng, Wenzhao
Zhang, Yiling
Huang, Jinhua
Xu, Lingling
Gou, Hongwei
Zeng, Linghui
Jin, Zhigang
Matsuoka, Masao
author_facet Zhao, Tiejun
Wang, Zhilong
Fang, Jinyong
Cheng, Wenzhao
Zhang, Yiling
Huang, Jinhua
Xu, Lingling
Gou, Hongwei
Zeng, Linghui
Jin, Zhigang
Matsuoka, Masao
author_sort Zhao, Tiejun
collection PubMed
description Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. HTLV-1 exerts its oncogenic functions by interacting with signaling pathways involved in cell proliferation and transformation. Dysregulation of the Hippo/YAP pathway is associated with multiple cancers, including virus-induced malignancies. In the present study, we observe that expression of YAP, which is the key effector of Hippo signaling, is elevated in ATL cells by the action of the HTLV-1 Tax protein. YAP transcriptional activity is remarkably enhanced in HTLV-1–infected cells and ATL patients. In addition, Tax activates the YAP protein via a mechanism involving the NF-κB/p65 pathway. As a mechanism for this cross talk between the Hippo and NF-κB pathways, we found that p65 abrogates the interaction between YAP and LATS1, leading to suppression of YAP phosphorylation, inhibition of ubiquitination-dependent degradation of YAP, and YAP nuclear accumulation. Finally, knockdown of YAP suppresses the proliferation of ATL cells in vitro and tumor formation in ATL-engrafted mice. Taken together, our results suggest that p65-induced YAP activation is essential for ATL pathogenesis and implicate YAP as a potential therapeutic target for ATL treatment.
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spelling pubmed-88923562022-08-24 HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis Zhao, Tiejun Wang, Zhilong Fang, Jinyong Cheng, Wenzhao Zhang, Yiling Huang, Jinhua Xu, Lingling Gou, Hongwei Zeng, Linghui Jin, Zhigang Matsuoka, Masao Proc Natl Acad Sci U S A Biological Sciences Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. HTLV-1 exerts its oncogenic functions by interacting with signaling pathways involved in cell proliferation and transformation. Dysregulation of the Hippo/YAP pathway is associated with multiple cancers, including virus-induced malignancies. In the present study, we observe that expression of YAP, which is the key effector of Hippo signaling, is elevated in ATL cells by the action of the HTLV-1 Tax protein. YAP transcriptional activity is remarkably enhanced in HTLV-1–infected cells and ATL patients. In addition, Tax activates the YAP protein via a mechanism involving the NF-κB/p65 pathway. As a mechanism for this cross talk between the Hippo and NF-κB pathways, we found that p65 abrogates the interaction between YAP and LATS1, leading to suppression of YAP phosphorylation, inhibition of ubiquitination-dependent degradation of YAP, and YAP nuclear accumulation. Finally, knockdown of YAP suppresses the proliferation of ATL cells in vitro and tumor formation in ATL-engrafted mice. Taken together, our results suggest that p65-induced YAP activation is essential for ATL pathogenesis and implicate YAP as a potential therapeutic target for ATL treatment. National Academy of Sciences 2022-02-24 2022-03-01 /pmc/articles/PMC8892356/ /pubmed/35210364 http://dx.doi.org/10.1073/pnas.2115316119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Zhao, Tiejun
Wang, Zhilong
Fang, Jinyong
Cheng, Wenzhao
Zhang, Yiling
Huang, Jinhua
Xu, Lingling
Gou, Hongwei
Zeng, Linghui
Jin, Zhigang
Matsuoka, Masao
HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis
title HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis
title_full HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis
title_fullStr HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis
title_full_unstemmed HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis
title_short HTLV-1 activates YAP via NF-κB/p65 to promote oncogenesis
title_sort htlv-1 activates yap via nf-κb/p65 to promote oncogenesis
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892356/
https://www.ncbi.nlm.nih.gov/pubmed/35210364
http://dx.doi.org/10.1073/pnas.2115316119
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