Chromatin Regulation By Ing3 Leads To Tumor Suppressive Effects In Pancreatic Cancer Through Distinct Signaling Pathways

Background: Despite our increased knowledge of the molecular events underlying the multi-step development of pancreatic cancer (PanCa), clinically meaningful improvement in survival rates has not yet been achieved. A growing body of evidence supports that pancreatic tumorigenesis is not only led by genetic alterations but also aberrant epigenetic regulation. Identification of epigenetic drivers of the clinical disease is of major importance, as it could potentially offer a means to interfere with novel targets in PanCa therapy. Methods: Gene expression microarrays were employed in PanCa tissues and adjacent uninvolved tissues. mRNA and protein levels were assessed by qRT-PCR and immunohistochemical analysis of tissue microarrays in extended cohorts of patients. RNAi interference assays or lentiviral expression vector systems were applied for knockdown/overexpression experiments, as evidenced by qRT-PCR and Western Blot Analysis. Molecular analysis, cell proliferation, invasion and colony formation assays were conducted in genetically modified cells. Subcutaneous xenograft mouse models were used to evaluate tumor growth in vivo. Immunoprecipitation followed by mass-spectroscopy analysis was used to evaluate protein-protein interactions. Histone H4 at lysine 16 acetylation (H4K16ac) levels were assessed by Western Blot analysis, while chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq) was performed for mapping protein-DNA interactions. Results: Differential expression analysis of chromatin regulators in PanCa versus normal tissues shows that 27 epigenetic molecules are significantly deregulated (u003e1.5 fold, P Conclusions: Conclusively, we provide evidence that PanCa is characterized by loss of the chromatin regulator ING3 and we elucidated the tumor suppressive role of the latter in PanCa cell growth and invasion in vitro and in vivo. Citation Format: Marina Koutsioumpa, Maria Hatziapostolou, Christos Polytarchou, Angelos Oikonomopoulos, Swapna Mahurkar-Joshi, Sara Huerta-Yepez, Belen Tirado-Rodriguez, Dimitrios Karavias, Helen Kourea, George A. Poultsides, David W. Dawson, Timothy R. Donahue, Dimitrios Iliopoulos. Chromatin regulation by ING3 leads to tumor suppressive effects in pancreatic cancer through distinct signaling pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4528.