Abstract 1439: Elucidation of the pathogenesis of prostate cancer harboring mutations of epigenetic factor UTX using genetically engineered mice

Abstract

Abstract Introduction and Objective: Histone modifications are important for tissue homeostasis, and their mutations are involved in carcinogenesis. Mutations in a histone modifier, UTX (KDM6A) are common in prostate cancer (PCa), which is frequently associated with loss of its counterpart UTY (KDM6C). However, mechanisms underlying the development of UTX-deficient PCa are not clear. We aimed to address this issue by generating and analyzing genetically-engineered mice. Methods: We generated mice with deletion of both Utx and Uty in the prostate tissue (UtxΔ, UtyΔ) and crossed with mice with a heterozygous deletion of p53 (p53+/−) to create UtxΔ, UtyΔ and p53+/− compound mice. High-fat diet (HFD) that is known to promote cancer growth was administered to mice. We found that UtxΔ, UtyΔ, p53+/− mice treated with HFD developed PCa with Gleason score (GS) = 3+3. Isolated prostate tissues were subjected to pathologic, molecular, and cellular analyses. In addition, RM-2 mouse PCa cells which do not express UTY were knocked down for Utx (siUtx) and control (siNC) by siRNAs to assess changes in the abilities of proliferation and migration. Results: RM-2 siUtx cells showed increased proliferation and migration compared with RM-2 siNC cells. By performing high-throughput RNA sequencing (RNA seq) and gene set enrichment analysis (GSEA) using mouse prostate tissues, we found that loss of UTX in the prostate activated inflammatory pathways, whereas inactivated DNA damage repair pathways. Immunostaining prostate tissues with an antibody to a macrophage marker, F4/80, exhibited significant accumulation of macrophages in UtxΔ, UtyΔ, p53+/+ mice compared to Utx+, UtyΔ, p53+/+ mice. In addition, immunofluorescent staining of irradiated prostate tissues with an antibody against a DNA repair marker, γH2AX, revealed that the time required for DNA damage repair was markedly prolonged in UtxΔ, UtyΔ, p53+/+ mice compared with Utx+, UtyΔ, p53+/+ mice. Conclusions: These results suggest that loss of UTX contributes to prostate cancer development through promoting inflammation and impairing DNA damage repair, which may serve as novel therapeutic targets in PCa patients with UTX mutations. Citation Format: NOBUHITO MURAMOTO, Masayuki Iwasaki, Yasuyuki Sera, Hisamitsu Ide, Shoichiro Mukai, Tsuyoshi Fukushima, Shigeo Horie, Hiroaki Honda. Elucidation of the pathogenesis of prostate cancer harboring mutations of epigenetic factor UTX using genetically engineered mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1439.