Abstract 6887: Targeting JMJD6: A Novel Approach in Cancer Therapy?

Abstract The Jumonji Domain Containing 6 protein (JMJD6) is part of the Jumonji C domain-containing protein family and functions as an arginine demethylase and lysine hydroxylase. JMJD6 facilitates demethylation of arginine and hydroxylation of lysine in both histone and non-histone proteins. Its activity on histones is primarily mediated by the JMJC domain, which is involved in demethylating H3R2me2 and H4R3me2. These demethylation events at histone H3 arginine 2 (H3R2me2) and histone H4 arginine 3 (H4R3me2) are crucial for regulating chromatin accessibility and gene transcription. JMJD6 also targets non-histone proteins such as TRAF6, STAT1, RNA helicase A, ERa, HSP70, EIF3B, EIF3C, etc. Additionally, more than 150 sites of JMJD6-catalyzed lysine hydroxylation on 48 protein substrates have been identified. JMJD6 plays an important role in transcriptional regulation, RNA splicing, inflammation, and immune responses. It downregulates pathways and activities like p53, TGF-β signaling, and Myc-induced apoptosis, while upregulating processes such as CDKs, WNT, MAPK, and autophagy pathways. Abnormal JMJD6 expression is linked to various diseases, including cancer. Elevated JMJD6 expression has been reported in many tumor types, including breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). High JMJD6 levels are also associated with poor prognosis, making it an attractive target for cancer therapy. In this study, we confirmed the critical role of JMJD6 in a NSCLC cell line and a liver cancer cell line. Using CRISPR/Cas9, we replaced the endogenous JMJD6 promoter with a doxycycline-regulated promoter, creating conditional JMJD6 cells. We will examine the effects of JMJD6 depletion in these cells and assess the complementation results with various JMJD6 alleles. Citation Format: Mathilde Calmels, Dorian Brager, Christophe Marcireau. Targeting JMJD6: A Novel Approach in Cancer Therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6887.