Cargando…

Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC

Pyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was...

Descripción completa

Detalles Bibliográficos
Autores principales: Chang, Hanyue, Xu, Qiaoshi, Li, Jiayi, Li, Mingyu, Zhang, Zhiyuan, Ma, Hailong, Yang, Xi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295286/
https://www.ncbi.nlm.nih.gov/pubmed/34290225
http://dx.doi.org/10.1038/s41419-021-03990-4
_version_ 1783725400947425280
author Chang, Hanyue
Xu, Qiaoshi
Li, Jiayi
Li, Mingyu
Zhang, Zhiyuan
Ma, Hailong
Yang, Xi
author_facet Chang, Hanyue
Xu, Qiaoshi
Li, Jiayi
Li, Mingyu
Zhang, Zhiyuan
Ma, Hailong
Yang, Xi
author_sort Chang, Hanyue
collection PubMed
description Pyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.
format Online
Article
Text
id pubmed-8295286
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-82952862021-08-05 Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC Chang, Hanyue Xu, Qiaoshi Li, Jiayi Li, Mingyu Zhang, Zhiyuan Ma, Hailong Yang, Xi Cell Death Dis Article Pyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC. Nature Publishing Group UK 2021-07-21 /pmc/articles/PMC8295286/ /pubmed/34290225 http://dx.doi.org/10.1038/s41419-021-03990-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Chang, Hanyue
Xu, Qiaoshi
Li, Jiayi
Li, Mingyu
Zhang, Zhiyuan
Ma, Hailong
Yang, Xi
Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC
title Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC
title_full Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC
title_fullStr Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC
title_full_unstemmed Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC
title_short Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC
title_sort lactate secreted by pkm2 upregulation promotes galectin-9-mediated immunosuppression via inhibiting nf-κb pathway in hnscc
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295286/
https://www.ncbi.nlm.nih.gov/pubmed/34290225
http://dx.doi.org/10.1038/s41419-021-03990-4
work_keys_str_mv AT changhanyue lactatesecretedbypkm2upregulationpromotesgalectin9mediatedimmunosuppressionviainhibitingnfkbpathwayinhnscc
AT xuqiaoshi lactatesecretedbypkm2upregulationpromotesgalectin9mediatedimmunosuppressionviainhibitingnfkbpathwayinhnscc
AT lijiayi lactatesecretedbypkm2upregulationpromotesgalectin9mediatedimmunosuppressionviainhibitingnfkbpathwayinhnscc
AT limingyu lactatesecretedbypkm2upregulationpromotesgalectin9mediatedimmunosuppressionviainhibitingnfkbpathwayinhnscc
AT zhangzhiyuan lactatesecretedbypkm2upregulationpromotesgalectin9mediatedimmunosuppressionviainhibitingnfkbpathwayinhnscc
AT mahailong lactatesecretedbypkm2upregulationpromotesgalectin9mediatedimmunosuppressionviainhibitingnfkbpathwayinhnscc
AT yangxi lactatesecretedbypkm2upregulationpromotesgalectin9mediatedimmunosuppressionviainhibitingnfkbpathwayinhnscc