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A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells
Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characterized by a highly conserved plant homeodomain (PHD) as a reader of the histone mark H3K4me3. ING3 was reported to act as a tumour suppressor in many different cancer types to regulate apoptosis. On the o...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392754/ https://www.ncbi.nlm.nih.gov/pubmed/34439818 http://dx.doi.org/10.3390/biom11081152 |
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author | Melekhova, Anna Leeder, Mirjam Pungsrinont, Thanakorn Schmäche, Tim Kallenbach, Julia Ehsani, Marzieh Mirzakhani, Kimia Rasa, Seyed Mohammad Mahdi Neri, Francesco Baniahmad, Aria |
author_facet | Melekhova, Anna Leeder, Mirjam Pungsrinont, Thanakorn Schmäche, Tim Kallenbach, Julia Ehsani, Marzieh Mirzakhani, Kimia Rasa, Seyed Mohammad Mahdi Neri, Francesco Baniahmad, Aria |
author_sort | Melekhova, Anna |
collection | PubMed |
description | Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characterized by a highly conserved plant homeodomain (PHD) as a reader of the histone mark H3K4me3. ING3 was reported to act as a tumour suppressor in many different cancer types to regulate apoptosis. On the other hand, ING3 levels positively correlate with poor survival prognosis of prostate cancer (PCa) patients. In PCa cells, ING3 acts rather as an androgen receptor (AR) co-activator and harbours oncogenic properties in PCa. Here, we show the identification of a novel ING3 splice variant in both the human PCa cell line LNCaP and in human PCa patient specimen. The novel ING3 splice variant lacks exon 11, ING3∆ex11, which results in deletion of the PHD, providing a unique opportunity to analyse functionally the PHD of ING3 by a natural splice variant. Functionally, overexpression of ING3Δex11 induced morphological changes of LNCaP-derived 3D spheroids with generation of lumen and pore-like structures within spheroids. Since these structures are an indicator of epithelial–mesenchymal transition (EMT), key regulatory factors and markers for EMT were analysed. The data suggest that in contrast to ING3, ING3Δex11 specifically modulates the expression of key EMT-regulating upstream transcription factors and induces the expression of EMT markers, indicating that the PHD of ING3 inhibits EMT. In line with this, ING3 knockdown also induced the expression of EMT markers, confirming the impact of ING3 on EMT regulation. Further, ING3 knockdown induced cellular senescence via a pathway leading to cell cycle arrest, indicating an oncogenic role for ING3 in PCa. Thus, the data suggest that the ING3Δex11 splice variant lacking functional PHD exhibits oncogenic characteristics through triggering EMT in PCa cells. |
format | Online Article Text |
id | pubmed-8392754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83927542021-08-28 A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells Melekhova, Anna Leeder, Mirjam Pungsrinont, Thanakorn Schmäche, Tim Kallenbach, Julia Ehsani, Marzieh Mirzakhani, Kimia Rasa, Seyed Mohammad Mahdi Neri, Francesco Baniahmad, Aria Biomolecules Article Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characterized by a highly conserved plant homeodomain (PHD) as a reader of the histone mark H3K4me3. ING3 was reported to act as a tumour suppressor in many different cancer types to regulate apoptosis. On the other hand, ING3 levels positively correlate with poor survival prognosis of prostate cancer (PCa) patients. In PCa cells, ING3 acts rather as an androgen receptor (AR) co-activator and harbours oncogenic properties in PCa. Here, we show the identification of a novel ING3 splice variant in both the human PCa cell line LNCaP and in human PCa patient specimen. The novel ING3 splice variant lacks exon 11, ING3∆ex11, which results in deletion of the PHD, providing a unique opportunity to analyse functionally the PHD of ING3 by a natural splice variant. Functionally, overexpression of ING3Δex11 induced morphological changes of LNCaP-derived 3D spheroids with generation of lumen and pore-like structures within spheroids. Since these structures are an indicator of epithelial–mesenchymal transition (EMT), key regulatory factors and markers for EMT were analysed. The data suggest that in contrast to ING3, ING3Δex11 specifically modulates the expression of key EMT-regulating upstream transcription factors and induces the expression of EMT markers, indicating that the PHD of ING3 inhibits EMT. In line with this, ING3 knockdown also induced the expression of EMT markers, confirming the impact of ING3 on EMT regulation. Further, ING3 knockdown induced cellular senescence via a pathway leading to cell cycle arrest, indicating an oncogenic role for ING3 in PCa. Thus, the data suggest that the ING3Δex11 splice variant lacking functional PHD exhibits oncogenic characteristics through triggering EMT in PCa cells. MDPI 2021-08-04 /pmc/articles/PMC8392754/ /pubmed/34439818 http://dx.doi.org/10.3390/biom11081152 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Melekhova, Anna Leeder, Mirjam Pungsrinont, Thanakorn Schmäche, Tim Kallenbach, Julia Ehsani, Marzieh Mirzakhani, Kimia Rasa, Seyed Mohammad Mahdi Neri, Francesco Baniahmad, Aria A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells |
title | A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells |
title_full | A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells |
title_fullStr | A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells |
title_full_unstemmed | A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells |
title_short | A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells |
title_sort | novel splice variant of the inhibitor of growth 3 lacks the plant homeodomain and regulates epithelial–mesenchymal transition in prostate cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392754/ https://www.ncbi.nlm.nih.gov/pubmed/34439818 http://dx.doi.org/10.3390/biom11081152 |
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