Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction

Abstract

Purpose: Epigenetic deregulation is deeply implicated in the pathogenesis of bladder cancer. KDM6A (Lysine (K)-specific demethylase 6A) is a histone modifier frequently mutated in bladder cancer. However, the molecular mechanisms of how KDM6A deficiency contributes to bladder cancer development remains largely unknown. We hypothesized that clarification of the pathogenic mechanisms underlying KDM6A-mutated bladder cancer can help in designing new anticancer therapies. Experimental Design: We generated mice lacking Kdm6a in the urothelium and crossed them with mice heterozygous for p53, whose mutation/deletion significantly overlaps with the KDM6A mutation in muscle-invasive bladder cancer (MIBC). In addition, BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine), a cigarette smoke-like mutagen, was used as a tumor-promoting agent. Isolated urothelia were subjected to phenotypic, pathologic, molecular, and cellular analyses. The clinical relevance of our findings was further analyzed using genomic and clinical data of patients with MIBC. Results: We found that Kdm6a deficiency activated cytokine and chemokine pathways, promoted M2 macrophage polarization, increased cancer stem cells and caused bladder cancer in cooperation with p53 haploinsufficiency. We also found that BBN treatment significantly enhanced the expression of proinflammatory molecules and accelerated disease development. Human bladder cancer samples with decreased KDM6A expression also showed activated proinflammatory pathways. Notably, dual inhibition of IL6 and chemokine (C-C motif) ligand 2, upregulated in response to Kdm6a deficiency, efficiently suppressed Kdm6a-deficient bladder cancer cell growth. Conclusions: Our findings provide insights into multistep carcinogenic processes of bladder cancer and suggest molecular targeted therapeutic approaches for patients with bladder cancer with KDM6A dysfunction.

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

“…These ndings support the need for further in-depth study of the possible role of KDM6A in regulation of cell adhesion and morphology in BC [21]. KDM6A de ciency has been suggested to activate pathways of chemokines and cytokines, increase M2 macrophage polarization, increase cancer stem cell abundance, and act synergistically with p53 haploinsu ciency [22]. Given the key function of KDM6A in regulating CD4 + T cells, [23] concluded that KDM6A likely regulates multiple immune response genes in autoimmune disease susceptibility.…”

Mutational Landscape and Environmental Effects in Bladder Cancer

“…The study using KDM6A-knockout bladder cancer cells and patient-derived xenograft model suggested that EZH2 (enhancer of zeste homolog 2, H3K27 methylase) inhibition is a potential therapeutic target for bladder cancer with the mutations [40]. In the recent study using the mice lacking Kdm6a in the urothelium, Kdm6a deficiency activates inflammatory pathways, promotes M2 macrophage polarization, and causes bladder cancer in cooperation with p53 dysfunction [41].…”

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

“…These ndings support the need for further in-depth study of the possible role of KDM6A in regulation of cell adhesion and morphology in BC [21]. KDM6A de ciency has been suggested to activate pathways of chemokines and cytokines, increase M2 macrophage polarization, increase cancer stem cell abundance, and act synergistically with p53 haploinsu ciency [22]. Given the key function of KDM6A in regulating CD4+ T cells [23],concluded that KDM6Alikely regulates multiple immune response genes in autoimmune disease susceptibility.…”