Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2

Abstract

Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in-null cell lines. EZH2 inhibition delayed tumor onset in -null cells and caused regression of-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

“…Recent studies have identified BRD4 - EZH2 chromatin modification as an important growth pathway in bladder cancer, especially in tumors with loss of KDM6A , and shown in preclinical models that the BET inhibitor JQ1 and inhibition of EZH2 have therapeutic benefit (Ler et al, 2017; Wu et al, 2016). Recently, a Phase 2 study of Mocetinostat, a histone deacetylase inhibitor, in patients with locally advanced or metastatic urothelial carcinoma has completed accrual and results are awaited (NCT02236195).…”

UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition

“…Importantly, a new set of cell lines we created in which UTX was disrupted by gene editing also showed increased sensitivity to EZH2i. Furthermore, the association between UTX loss and increased response to EZH2i was also observed in bladder cancer cells (Ler et al, 2017). This suggests several cancer types harboring loss of UTX may be susceptible of therapeutic intervention with these drugs.…”

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

“…This suggests that SARC evolved from precursor conventional UC carrying these mutations and that mutations in these genes may drive the progression process. Several of the genes that are frequently mutated in conventional UC, including ARID1A , KDM6A , EP300 , ELF3 , and CREBBP , were not mutated in SARC, and these genes are involved in chromatin remodeling (Dutto et al, 2018; Ler et al, 2017; Skulte et al, 2014; Tang et al, 2013; Wang et al, 2017; Zheng et al, 2018). In general, as a group, chromatin-remodeling genes were not mutated in SARC.…”