Epigenomic study identifies a novel mesenchyme homeobox2-GLI1 transcription axis involved in cancer drug resistance, overall survival and therapy prognosis in lung cancer patients
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Leonel Armas-López1, Patricia Piña-Sánchez2, Oscar Arrieta3, Enrique Guzman de Alba4, Blanca Ortiz-Quintero4, Patricio Santillán-Doherty4, David C. Christiani5, Joaquín Zúñiga4 and Federico Ávila-Moreno1,4
1National University Autonomous of México (UNAM), Facultad de Estudios Superiores (FES) Iztacala, Biomedicine Research Unit (UBIMED), Lung Diseases And Cancer Epigenomics Laboratory, Mexico State, Mexico
2Instituto Mexicano del Seguro Social (IMSS), Centro Medico Nacional (CMN) Siglo XXI, Unidad de Investigación Médica en Enfermedades Oncológicas (UIMEO), Molecular Oncology Laboratory, Mexico City, Mexico
3National Cancer Institute (INCAN), Thoracic Oncology Clinic, Mexico City, Mexico
4National Institute of Respiratory Diseases (INER) “Ismael Cosío Villegas”, Mexico City, Mexico
5Harvard Medical School, Harvard School of Public Health, Department of Environmental Health, Boston, Massachusetts, USA
Keywords: lung cancer, homeobox transcription factors, epigenetics cancer drug resistance, overall survival, treatment prognosis
Received: May 26, 2016 Accepted: April 11, 2017 Published: May 09, 2017
Several homeobox-related gene (HOX) transcription factors such as mesenchyme HOX-2 (MEOX2) have previously been associated with cancer drug resistance, malignant progression and/or clinical prognostic responses in lung cancer patients; however, the mechanisms involved in these responses have yet to be elucidated. Here, an epigenomic strategy was implemented to identify novel MEOX2 gene promoter transcription targets and propose a new molecular mechanism underlying lung cancer drug resistance and poor clinical prognosis. Chromatin immunoprecipitation (ChIP) assays derived from non-small cell lung carcinomas (NSCLC) hybridized on gene promoter tiling arrays and bioinformatics analyses were performed, and quantitative, functional and clinical validation were also carried out. We statistically identified a common profile consisting of 78 gene promoter targets, including Hedgehog-GLI1 gene promoter sequences (FDR≤0.1 and FDR≤0.2). The GLI-1 gene promoter region from -2,192 to -109 was occupied by MEOX2, accompanied by transcriptionally active RNA Pol II and was epigenetically linked to the active histones H3K27Ac and H3K4me3; these associations were quantitatively validated. Moreover, siRNA genetic silencing assays identified a MEOX2-GLI1 axis involved in cellular cytotoxic resistance to cisplatinum in a dose-dependent manner, as well as cellular migration and proliferation. Finally, Kaplan-Maier survival analyses identified significant MEOX2-dependent GLI-1 protein expression associated with clinical progression and poorer overall survival using an independent cohort of NSCLC patients undergoing platinum-based oncological therapy with both epidermal growth factor receptor (EGFR)-non-mutated and EGFR-mutated status. In conclusion, this is the first study to investigate epigenome-wide MEOX2-transcription factor occupation identifying a novel overexpressed MEOX2-GLI1 axis and its clinical association with platinum-based cancer drug resistance and EGFR-tyrosine kinase inhibitor (TKI)-based therapy responses in NSCLC patients.
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