Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis
<i>Iroquois homeobox</i> (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the <i>IRX1</i> gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and functio...
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2020-11-01
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Miriam M. Küster Marc A. Schneider Antje M. Richter Sarah Richtmann Hauke Winter Mark Kriegsmann Soni S. Pullamsetti Thorsten Stiewe Rajkumar Savai Thomas Muley Reinhard H. Dammann |
spellingShingle |
Miriam M. Küster Marc A. Schneider Antje M. Richter Sarah Richtmann Hauke Winter Mark Kriegsmann Soni S. Pullamsetti Thorsten Stiewe Rajkumar Savai Thomas Muley Reinhard H. Dammann Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis Cancers IRX DNA methylation epigenetic lung cancer adenocarcinoma apoptosis |
author_facet |
Miriam M. Küster Marc A. Schneider Antje M. Richter Sarah Richtmann Hauke Winter Mark Kriegsmann Soni S. Pullamsetti Thorsten Stiewe Rajkumar Savai Thomas Muley Reinhard H. Dammann |
author_sort |
Miriam M. Küster |
title |
Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis |
title_short |
Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis |
title_full |
Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis |
title_fullStr |
Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis |
title_full_unstemmed |
Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis |
title_sort |
epigenetic inactivation of the tumor suppressor <i>irx1</i> occurs frequently in lung adenocarcinoma and its silencing is associated with impaired prognosis |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-11-01 |
description |
<i>Iroquois homeobox</i> (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the <i>IRX1</i> gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the <i>IRX1</i> promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant <i>IRX1</i> methylation was significantly correlated with reduced <i>IRX1</i> expression. In normal lung samples, the <i>IRX1</i> promoter showed lower median DNA methylation levels (<10%) compared to primary adenocarcinoma (ADC, 22%) and squamous cell carcinoma (SQCC, 14%). A significant hypermethylation and downregulation of <i>IRX1</i> was detected in ADC and SQCC compared to matching normal lung samples (<i>p </i>< 0.0001). Low <i>IRX1</i> expression was significantly correlated with impaired prognosis of ADC patients (<i>p </i>= 0.001). Reduced survival probability was also associated with higher <i>IRX1</i> promoter methylation (<i>p </i>= 0.02). Inhibition of DNA methyltransferase (DNMT) activity reactivated <i>IRX1</i> expression in human lung cancer cell lines. Induced DNMT3A and EZH2 expression was correlated with downregulation of <i>IRX1</i>. On the cellular level, IRX1 exhibits nuclear localization and expression of IRX1 induced fragmented nuclei in cancer cells. Localization of IRX1 and induction of aberrant nuclei were dependent on the presence of the homeobox of IRX1. By data mining, we showed that <i>IRX1</i> is negatively correlated with oncogenic pathways and <i>IRX1</i> expression induces the proapoptotic regulator <i>BAX</i>. In conclusion, we report that <i>IRX1</i> expression is significantly associated with improved survival probability of ADC patients. <i>IRX1</i> hypermethylation may serve as molecular biomarker for ADC diagnosis and prognosis. Our data suggest that <i>IRX1</i> acts as an epigenetically regulated tumor suppressor in the pathogenesis of lung cancer. |
topic |
IRX DNA methylation epigenetic lung cancer adenocarcinoma apoptosis |
url |
https://www.mdpi.com/2072-6694/12/12/3528 |
work_keys_str_mv |
AT miriammkuster epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT marcaschneider epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT antjemrichter epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT sarahrichtmann epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT haukewinter epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT markkriegsmann epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT sonispullamsetti epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT thorstenstiewe epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT rajkumarsavai epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT thomasmuley epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis AT reinhardhdammann epigeneticinactivationofthetumorsuppressoriirx1ioccursfrequentlyinlungadenocarcinomaanditssilencingisassociatedwithimpairedprognosis |
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doaj-f8123b49cc8645a58b8a4d8f26fd850e2020-11-27T08:10:58ZengMDPI AGCancers2072-66942020-11-01123528352810.3390/cancers12123528Epigenetic Inactivation of the Tumor Suppressor <i>IRX1</i> Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired PrognosisMiriam M. Küster0Marc A. Schneider1Antje M. Richter2Sarah Richtmann3Hauke Winter4Mark Kriegsmann5Soni S. Pullamsetti6Thorsten Stiewe7Rajkumar Savai8Thomas Muley9Reinhard H. Dammann10Faculty of Biology, Institute for Genetics, Justus-Liebig-University Giessen, 35392 Giessen, GermanyTranslational Research Unit, Thoraxklinik at Heidelberg University Hospital, 69126 Heidelberg, GermanyFaculty of Biology, Institute for Genetics, Justus-Liebig-University Giessen, 35392 Giessen, GermanyTranslational Research Unit, Thoraxklinik at Heidelberg University Hospital, 69126 Heidelberg, GermanyUniversities of Giessen and Marburg Lung Center (UGMLC) and Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Center (UGMLC) and Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Center (UGMLC) and Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Center (UGMLC) and Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Center (UGMLC) and Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), 35392 Giessen, GermanyTranslational Research Unit, Thoraxklinik at Heidelberg University Hospital, 69126 Heidelberg, GermanyFaculty of Biology, Institute for Genetics, Justus-Liebig-University Giessen, 35392 Giessen, Germany<i>Iroquois homeobox</i> (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the <i>IRX1</i> gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the <i>IRX1</i> promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant <i>IRX1</i> methylation was significantly correlated with reduced <i>IRX1</i> expression. In normal lung samples, the <i>IRX1</i> promoter showed lower median DNA methylation levels (<10%) compared to primary adenocarcinoma (ADC, 22%) and squamous cell carcinoma (SQCC, 14%). A significant hypermethylation and downregulation of <i>IRX1</i> was detected in ADC and SQCC compared to matching normal lung samples (<i>p </i>< 0.0001). Low <i>IRX1</i> expression was significantly correlated with impaired prognosis of ADC patients (<i>p </i>= 0.001). Reduced survival probability was also associated with higher <i>IRX1</i> promoter methylation (<i>p </i>= 0.02). Inhibition of DNA methyltransferase (DNMT) activity reactivated <i>IRX1</i> expression in human lung cancer cell lines. Induced DNMT3A and EZH2 expression was correlated with downregulation of <i>IRX1</i>. On the cellular level, IRX1 exhibits nuclear localization and expression of IRX1 induced fragmented nuclei in cancer cells. Localization of IRX1 and induction of aberrant nuclei were dependent on the presence of the homeobox of IRX1. By data mining, we showed that <i>IRX1</i> is negatively correlated with oncogenic pathways and <i>IRX1</i> expression induces the proapoptotic regulator <i>BAX</i>. In conclusion, we report that <i>IRX1</i> expression is significantly associated with improved survival probability of ADC patients. <i>IRX1</i> hypermethylation may serve as molecular biomarker for ADC diagnosis and prognosis. Our data suggest that <i>IRX1</i> acts as an epigenetically regulated tumor suppressor in the pathogenesis of lung cancer.https://www.mdpi.com/2072-6694/12/12/3528IRXDNA methylationepigeneticlung canceradenocarcinomaapoptosis |