Abstract 1962: Regulation of invasion by lysine demethylase 5B in non-small cell lung cancer cells

Abstract

Histone modifying enzymes are often dysregulated during carcinogenesis and are major contributors to the development of oncogenic features, including proliferation, drug resistance, and metastasis. Given these roles, histone modifiers are promising new targets for oncological therapeutics. One of the enzyme families at the center of this area of research is the lysine demethylase family KDM5, for which several inhibitors are in development. KDM5A and KDM5B are frequently overexpressed or mutated in human non-small cell lung cancer (NSCLC). In overexpression studies, KDM5B promotes invasion and migration of NSCLC cells, whereas invasion and migration of NSCLC cells were decreased following knockdown of KDM5B. Furthermore, in patients with NSCLC, KDM5B is expressed at higher levels in brain metastasis sites when compared to both normal tissues and primary tumors. These findings suggest a role for KDM5B in lung cancer and metastatic spread. However, the precise role of KDM5 family members in lung cancer invasion and metastasis is not known. Recently, we discovered that KDM5B is differentially expressed in cell subtypes within a 3D model of NSCLC collective cell invasion. In this model isolated single cells at the forefront of invasive branches (leader cells) express more 2-4 fold more KDM5B protein than the cells following (follower cells), while KDM5A and KDM5C are evenly expressed across both cell types. KDM5B mRNA expression is similar across cell types suggesting that the differential protein expression is mediated at the posttranscriptional level. Interestingly, global H3K4me3 levels are decreased in leader cells as compared to follower cells, supporting the idea that the lysine demethylases targeting this residue may be expressed at higher levels in leader cells. Collectively, these data suggest that KDM5B could be contributing to initiation of invasion at the primary site and thus, promoting metastasis. Given the rising prominence of therapeutic inhibitors of KDM5 family members, a better understanding how KDM5B contributes to cell invasion may lead to a new approach to the prevention of metastasis. Citation Format: Elizabeth L. Zoeller, Jessica Konen, Joshua Bell, Emily Summerbell, Jeanne Kowalski, Adam Marcus, Paula Vertino. Regulation of invasion by lysine demethylase 5B in non-small cell lung cancer cells [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 1962. doi:10.1158/1538-7445.AM2017-1962