Abstract 1752: Inhibition of histone demethylase KDM6B as a promising target for non-small cell lung cancer

Abstract

Despite advances in diagnostic and therapeutic approaches, the majority of lung cancer patients still progress to advanced stages with metastatic lesions. Abnormalities in epigenetic mechanisms are related to the most malignant cancer phenotypes. Thus, there is an increasing interest in the development and validation of drugs that targets epigenetic proteins. Trimethylation of H3K27 is an important post-translational modification and some studies have shown that KDM6B (lysine (K)-specific demethylase 6B), an H3K27 demethylase, is a crucial regulator involved in tumorigenesis and play important roles in various types of cancers. In this study, our goal was to determine potential epigenetic targets to control invasion and migration of NSCLC cancer cells. Initially, KDM6B was found a promise target through in silico analysis for the inverse correlation between gene expression and overall survival on 2438 NSCLC cases from GEO, EGA and TCGA using KMplotter tool and selecting the genes according to HR and p-values (HR > 1 and p < 0.05). Next, NSCLC cell lines (A549, H23, H2126 and H1568) were evaluated for the expression of the KDM6B using CellExpress tool and next by real-time PCR and one cell was chosen for cytotoxicity of the KDM6B inhibitor (GSK-J4) for 72h by MTT assay. The IC50 value and the regression curve were calculated with 6.0 Prism (GraphPad Software, USA). KDM6B gene expression was inversely correlated with patient survival rate for pulmonary adenocarcinoma (HR= 2.81; p= 6,3E-09). All pulmonary adenocarcinoma cell lines expressed KDM6B gene and low expression in healthy lung tissue (Z-score= 2.8). The KDM6B IC50 for A549 cells was 2.78±0.09μM. These early findings report that KDM6B as a promising target for epigenetic therapy for pulmonary adenocarcinoma. Therefore, our next step will be to evaluate the potential of KDM6B inhibition on the phenotype of cancer cell migration and invasion and global analysis of gene expression to understand genes and mechanisms associated with possible inhibitory effects of KDM6B. Citation Format: Jessika C. Lesbon, Pedro L. Xavier, Taismara K. Garnica, Arina L. Rochetti, Rui M. Reis, Susanne Müller, Heidge Fukumasu. Inhibition of histone demethylase KDM6B as a promising target for non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1752.