Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes
T-box (TBX) transcription factors are evolutionary conserved genes and master transcriptional regulators. In mammals, TBX2 subfamily (TBX2, TBX3, TBX4, and TBX5) genes are expressed in the developing lung bud and tracheae. Our group previously showed that the expression of TBX2 subfamily was signifi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2018.00482/full |
| _version_ | 1811303701849047040 |
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| author | Athar Khalil Batoul Dekmak Fouad Boulos Jake Kantrowitz Avrum Spira Junya Fujimoto Humam Kadara Humam Kadara Nehme El-Hachem Georges Nemer |
| author_facet | Athar Khalil Batoul Dekmak Fouad Boulos Jake Kantrowitz Avrum Spira Junya Fujimoto Humam Kadara Humam Kadara Nehme El-Hachem Georges Nemer |
| author_sort | Athar Khalil |
| collection | DOAJ |
| description | T-box (TBX) transcription factors are evolutionary conserved genes and master transcriptional regulators. In mammals, TBX2 subfamily (TBX2, TBX3, TBX4, and TBX5) genes are expressed in the developing lung bud and tracheae. Our group previously showed that the expression of TBX2 subfamily was significantly high in human normal lungs, but markedly suppressed in lung adenocarcinoma (LUAD). To further elucidate their role in LUAD pathogenesis, we first confirmed abundant expression of protein products of the four members by immunostaining in adult human normal lung tissues. We also found overall suppressed expression of these genes and their corresponding proteins in a panel of human LUAD cell lines. Transient over-expression of each of the genes in human (NCI-H1299), and mouse (MDA-F471) derived lung cancer cells was found to significantly inhibit growth and proliferation as well as induce apoptosis. Genome-wide transcriptomic analyses on NCI-H1299 cells, overexpressing TBX2 gene subfamily, unraveled novel regulatory pathways. These included, among others, inhibition of cell cycle progression but more importantly activation of the histone demethylase pathway. When using a pattern-matching algorithm, we showed that TBX's overexpression mimic molecular signatures from azacitidine treated NCI-H1299 cells which in turn are inversely correlated to expression profiles of both human and murine lung tumors relative to matched normal lung. In conclusion, we showed that the TBX2 subfamily genes play a critical tumor suppressor role in lung cancer pathogenesis through regulating its methylating pattern, making them putative candidates for epigenetic therapy in LUAD. |
| first_indexed | 2024-04-13T07:52:45Z |
| format | Article |
| id | doaj.art-919c6233be214886bce31a382a27c960 |
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| language | English |
| last_indexed | 2024-04-13T07:52:45Z |
| publishDate | 2018-10-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-919c6233be214886bce31a382a27c9602022-12-22T02:55:29ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2018-10-01810.3389/fonc.2018.00482417890Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor GenesAthar Khalil0Batoul Dekmak1Fouad Boulos2Jake Kantrowitz3Avrum Spira4Junya Fujimoto5Humam Kadara6Humam Kadara7Nehme El-Hachem8Georges Nemer9Departments of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartments of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartment of Pathology, Faculty of Medicine, American University of Beirut, Beirut, LebanonSection of Computational Biomedicine, Boston University, Boston, MA, United StatesSection of Computational Biomedicine, Boston University, Boston, MA, United StatesDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartments of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, LebanonDivision of Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesFaculty of Medicine and Genome Innovation Centre, McGill University, Montreal, QC, CanadaDepartments of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, LebanonT-box (TBX) transcription factors are evolutionary conserved genes and master transcriptional regulators. In mammals, TBX2 subfamily (TBX2, TBX3, TBX4, and TBX5) genes are expressed in the developing lung bud and tracheae. Our group previously showed that the expression of TBX2 subfamily was significantly high in human normal lungs, but markedly suppressed in lung adenocarcinoma (LUAD). To further elucidate their role in LUAD pathogenesis, we first confirmed abundant expression of protein products of the four members by immunostaining in adult human normal lung tissues. We also found overall suppressed expression of these genes and their corresponding proteins in a panel of human LUAD cell lines. Transient over-expression of each of the genes in human (NCI-H1299), and mouse (MDA-F471) derived lung cancer cells was found to significantly inhibit growth and proliferation as well as induce apoptosis. Genome-wide transcriptomic analyses on NCI-H1299 cells, overexpressing TBX2 gene subfamily, unraveled novel regulatory pathways. These included, among others, inhibition of cell cycle progression but more importantly activation of the histone demethylase pathway. When using a pattern-matching algorithm, we showed that TBX's overexpression mimic molecular signatures from azacitidine treated NCI-H1299 cells which in turn are inversely correlated to expression profiles of both human and murine lung tumors relative to matched normal lung. In conclusion, we showed that the TBX2 subfamily genes play a critical tumor suppressor role in lung cancer pathogenesis through regulating its methylating pattern, making them putative candidates for epigenetic therapy in LUAD.https://www.frontiersin.org/article/10.3389/fonc.2018.00482/fulltranscriptomicsT-Boxtumor suppressor genedemethylationlung adenocarcinoma |
| spellingShingle | Athar Khalil Batoul Dekmak Fouad Boulos Jake Kantrowitz Avrum Spira Junya Fujimoto Humam Kadara Humam Kadara Nehme El-Hachem Georges Nemer Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes Frontiers in Oncology transcriptomics T-Box tumor suppressor gene demethylation lung adenocarcinoma |
| title | Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes |
| title_full | Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes |
| title_fullStr | Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes |
| title_full_unstemmed | Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes |
| title_short | Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes |
| title_sort | transcriptomic alterations in lung adenocarcinoma unveil new mechanisms targeted by the tbx2 subfamily of tumor suppressor genes |
| topic | transcriptomics T-Box tumor suppressor gene demethylation lung adenocarcinoma |
| url | https://www.frontiersin.org/article/10.3389/fonc.2018.00482/full |
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