RRC ID 58397
Author Kobatake K, Ikeda KI, Nakata Y, Yamasaki N, Ueda T, Kanai A, Sentani K, Sera Y, Hayashi T, Koizumi M, Miyakawa Y, Inaba T, Sotomaru Y, Kaminuma O, Ichinohe T, Honda ZI, Yasui W, Horie S, Black PC, Matsubara A, Honda H.
Title Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction.
Journal Clin Cancer Res
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.
Volume 26(8)
Pages 2065-2079
Published 2020-4-15
DOI 10.1158/1078-0432.CCR-19-2230
PII 1078-0432.CCR-19-2230
PMID 32047002
MeSH Animals Carcinogenesis / genetics Carcinogenesis / immunology Carcinogenesis / pathology* Databases, Genetic / statistics & numerical data Disease Models, Animal Histone Demethylases / physiology* Humans Inflammation / genetics Inflammation / immunology Inflammation / metabolism Inflammation / pathology* Macrophages / immunology* Mice Mice, Inbred C3H Mice, Knockout Tumor Suppressor Protein p53 / physiology* Urinary Bladder Neoplasms / genetics Urinary Bladder Neoplasms / immunology Urinary Bladder Neoplasms / metabolism Urinary Bladder Neoplasms / pathology* Urothelium / immunology Urothelium / pathology*
IF 10.107
Times Cited 0
Mice RBRC01361