Abstract 682: Novel Mesenchyme Homeobox2-target transcription axes are involved in cancer-drug resistance, overall survival and therapy prognosis in lung cancer patients: a functional epigenome wide study

Abstract

Abstract Lung cancer remains the most progressive malignant disease strongly resistant to oncological therapies including platinum-derived cancer drugs and Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinases Inhibitors (TKIs). Homeobox-related gene (HOX) transcription factors as Mesenchyme HOX-2 (MEOX2) have previously been associated with cancer-drug resistance, progression and/or clinical prognosis in lung cancer patients. However, transcriptional mechanisms epigenetically modulated have not totally been elucidated in lung cancer therapy resistance. Here an epigenomic strategy was conducted to identify a novel MEOX2 gene sequence-promoter targets profile, associated or involved in therapy resistance mechanisms in human lung cancer. For that chromatin from human non-small cell lung carcinomas (NSCLC), MEOX2 versus RNA Pol II immunoprecipitation and hybridization assays using gene promoter tiling-arrays and bioinformatics analyses were performed, while a set of quantitative and functional assays with clinical-outcome prognosis validation predictions analyses, were assessed. Stringent bioinformatics results identified a common profile of 13 gene promoter sequences, which included in others Sonic Hedgehog-GLI-1, ALDH1A2, MMP24, RUFY3 and ZEB1 (FDR≤0.1) in NSCLC patients with different clinical outcome data. GLI-1 gene promoter-sequences upstream -2,192 to -109 quantitatively validated, were occupied by MEOX2 and RNA Pol II in both NSCLC cell lines and NSCLC patients, as well as consistently enriched with the histone activation marks H3K27Ac and H3K4me3, in addition, confirmed by the ENCODE database bioinformatics analyses. Furthermore, a set of genetic silencing functional assays validated a novel transcriptional MEOX2-GLI1 axis in a cisplatinum dose-dependent manner, involved in cellular migration, invasion, and proliferation capacity. Finally, MEOX2-GLI1 axis expression was clinically validated and analyzed using Kaplan-Maier survival analyses on an independent cohort of 90 NSCLC patients, identifying a significant MEOX2-dependent GLI-1 overexpression statistically associated with clinical poorer overall survival prognosis and treatment response into cisplatinum-based first-line therapy and/or second-line EGFR-TKIs target therapy protocols. In conclusion, a chromatin-immunoprecipitation and epigenome-wide analysis based on the MEOX2-transcriptional occupation study, identified novel MEOX2-transcriptional gene promoter axes involved in embryonic development, oxidoreductase activity, matrix metalloprotease, cellular polarity, epithelial-mesenchyme phenotype, cancer cell migration and invasion pathways. Promoting cisplatinum-based resistance mechanisms and EGFR-TKIs based therapy response prognosis in human lung cancer. Note: This abstract was not presented at the meeting. Citation Format: Federico Avila Moreno, Leonel Armas lopez, Patricia Piña-Sánchez, Oscar Arrieta, Enrique Gúzman de Alba, Abril Marcela Herrera-Solorio, Blanca Ortiz-Quintero, Patricio Santillán-Doherty, David C Christiani, Joaquín Zúñiga. Novel Mesenchyme Homeobox2-target transcription axes are involved in cancer-drug resistance, overall survival and therapy prognosis in lung cancer patients: a functional epigenome wide study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 682. doi:10.1158/1538-7445.AM2017-682