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PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK
Prolyl hydroxylase 3 (PHD3) hydroxylates HIFα in the presence of oxygen, leading to HIFα degradation. PHD3 inhibits tumorigenesis. However, the underlying mechanism is not well understood. Herein, we demonstrate that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 MAPK pa...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10679873/ https://www.ncbi.nlm.nih.gov/pubmed/37814811 http://dx.doi.org/10.3724/abbs.2023103 |
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author | Li, Yuyao Yuan, Tanglong Zhang, Hongwei Liu, Shuting Lun, Jie Guo, Jing Wang, Yu Zhang, Yuying Fang, Jing |
author_facet | Li, Yuyao Yuan, Tanglong Zhang, Hongwei Liu, Shuting Lun, Jie Guo, Jing Wang, Yu Zhang, Yuying Fang, Jing |
author_sort | Li, Yuyao |
collection | PubMed |
description | Prolyl hydroxylase 3 (PHD3) hydroxylates HIFα in the presence of oxygen, leading to HIFα degradation. PHD3 inhibits tumorigenesis. However, the underlying mechanism is not well understood. Herein, we demonstrate that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 MAPK pathway independent of its hydroxylase activity. We find that PHD3 inhibits colon cancer cell metastasis in the presence of the PHD inhibitor DMOG, and prolyl hydroxylase-deficient PHD3(H196A) suppresses cell metastasis as well. PHD3 controls the stability of the tight junction protein occludin in a hydroxylase-independent manner. We further find that PHD3-inhibited colon cancer cell metastasis is rescued by knockdown of occludin and that occludin acts as a negative regulator of cell metastasis, implying that PHD3 suppresses metastasis through occludin. Furthermore, knockdown of occludin induces phosphorylation of p38 MAPK, and the p38 inhibitor SB203580 impedes cell migration and invasion induced by occludin knockdown, indicating that occludin functions through p38. Moreover, knockdown of occludin enhances the expression of MKK3/6, the upstream kinase of p38, while overexpression of occludin decreases its expression. Our results suggest that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 pathway independent of its hydroxylase activity. These findings reveal a previously undiscovered mechanism underlying the regulation of cancer cell metastasis by PHD3 and highlight a noncanonical hydroxylase-independent function of PHD3 in the suppression of cancer cells. |
format | Online Article Text |
id | pubmed-10679873 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106798732023-10-09 PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK Li, Yuyao Yuan, Tanglong Zhang, Hongwei Liu, Shuting Lun, Jie Guo, Jing Wang, Yu Zhang, Yuying Fang, Jing Acta Biochim Biophys Sin (Shanghai) Research Article Prolyl hydroxylase 3 (PHD3) hydroxylates HIFα in the presence of oxygen, leading to HIFα degradation. PHD3 inhibits tumorigenesis. However, the underlying mechanism is not well understood. Herein, we demonstrate that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 MAPK pathway independent of its hydroxylase activity. We find that PHD3 inhibits colon cancer cell metastasis in the presence of the PHD inhibitor DMOG, and prolyl hydroxylase-deficient PHD3(H196A) suppresses cell metastasis as well. PHD3 controls the stability of the tight junction protein occludin in a hydroxylase-independent manner. We further find that PHD3-inhibited colon cancer cell metastasis is rescued by knockdown of occludin and that occludin acts as a negative regulator of cell metastasis, implying that PHD3 suppresses metastasis through occludin. Furthermore, knockdown of occludin induces phosphorylation of p38 MAPK, and the p38 inhibitor SB203580 impedes cell migration and invasion induced by occludin knockdown, indicating that occludin functions through p38. Moreover, knockdown of occludin enhances the expression of MKK3/6, the upstream kinase of p38, while overexpression of occludin decreases its expression. Our results suggest that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 pathway independent of its hydroxylase activity. These findings reveal a previously undiscovered mechanism underlying the regulation of cancer cell metastasis by PHD3 and highlight a noncanonical hydroxylase-independent function of PHD3 in the suppression of cancer cells. Oxford University Press 2023-10-09 /pmc/articles/PMC10679873/ /pubmed/37814811 http://dx.doi.org/10.3724/abbs.2023103 Text en © The Author(s) 2021. 0 https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Li, Yuyao Yuan, Tanglong Zhang, Hongwei Liu, Shuting Lun, Jie Guo, Jing Wang, Yu Zhang, Yuying Fang, Jing PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK |
title | PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK |
title_full | PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK |
title_fullStr | PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK |
title_full_unstemmed | PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK |
title_short | PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: PHD3 inhibits metastasis via occludin-p38 MAPK |
title_sort | phd3 inhibits colon cancer cell metastasis through the occludin-p38 pathway: phd3 inhibits metastasis via occludin-p38 mapk |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10679873/ https://www.ncbi.nlm.nih.gov/pubmed/37814811 http://dx.doi.org/10.3724/abbs.2023103 |
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