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.

Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. Here, we show that UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of Compass-like and SWI/SNF complexes, plays an essential role in the hematopoietic system by globally regulating aging-associated genes. Utx-deficient (UtxΔ/Δ) mice exhibited myeloid skewing with dysplasia, extramedullary hematopoiesis, impaired hematopoietic reconstituting ability, and increased susceptibility to leukemia, which are the hallmarks of hematopoietic aging. RNA-sequencing (RNA-seq) analysis revealed that Utx deficiency converted the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. Utx expression in HSCs declines with age and UtxΔ/Δ HSPCs exhibited increased expression of an aging-associated marker, accumulation of reactive oxygen species, and impaired repair of DNA double-strand breaks. Pathway and chromatin immunoprecipitation (ChIP) analyses coupled with RNA-seq data indicated that UTX contributes to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging, via both demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged iPS-induced neuronal cells showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells.

Tumour lysis syndrome (TLS) and choriocarcinoma syndrome (CS) are severe complications of chemotherapy for testicular cancer. They are rare, but can be life-threatening. A 37-year-old man complaining of persisting cough was referred to our hospital. A computed tomography (CT) scan revealed huge tumours that occupied the peritoneal cavity, with multiple lung, liver, and para-aortic metastases. Although there was no abnormal finding in the testes, serum testicular tumor markers showed marked elevation. A CT-guided biopsy for the peritoneal tumours revealed extragonadal germ cell tumour (GCT), including yolk sac tumour and choriocarcinoma. Chemotherapy with bleomycin, etoposide, and cisplatin (BEP) was started after admission. The morning after the beginning of BEP, the patient developed hemorrhagic shock, in addition to acute pulmonary and renal failure, because of TLS and massive hemorrhage at bilateral lung metastases. He was intubated and resuscitated. Despite appropriate therapy, his renal function did not recover and hemodialysis was started. The patient eventually died of severe respiratory distress syndrome and infection. To our knowledge, this is the first case report of TLS and CS as complications of hemorrhage at the lung metastases of advanced testicular cancer leading to death.

Abstract. The aim of the present study was to compare the benefits of transurethral resection (TUR) under narrow band imaging (NBI-TUR) and TUR under conventional white light imaging (WLI-TUR) for non-muscle invasive bladder cancer (NMIBC). The study cohort consisted of 135 patients with NMIBC who were followed up for ≥1 year after TUR and who received no additional post-operative treatment. In the WLI-TUR group (n=78), systematic intravesical observation under WLI was followed by a multiple site biopsy (MSB), after which lesions detected as positive findings were resected completely under WLI. In the NBI-TUR group (n=57), similar observation under WLI was followed by systematic intravesical observation under NBI. Following MSB under NBI, TUR was performed for all lesions detected as positive findings under NBI. The sensitivity, specificity, positive-predictive value, negative-predictive value (NPV) and accuracy in the NBI-TUR group were calculated using results from the cystoscopical and pathological examinations of MSB samples under WLI and NBI. The tumor recurrence rate was analyzed in the two groups. Background factors did not differ significantly between the two groups, with the exception of the observation period (31.0 vs. 15.0 months; P<0.01). The procedure under NBI exhibited significantly higher sensitivity (95.0 vs. 70.0%; P<0.01) and NPV (97.1 vs. 86.8%; P<0.01) compared with the procedure under WLI. The 1-year recurrence rate in the NBI-TUR group was significantly lower than that in the WLI-TUR group (21.1 vs. 39.7%; P=0.016). In conclusion, the present study indicated that NBI-TUR is more advantageous than conventional WLI-TUR for patients with NMIBC.

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