(UroToday.com) Consensus transcriptomic subtypes of bladder cancer have previously been proposed, separating the disease into two major subgroups - Luminal and Basal. Each subtype presents distinct molecular and clinical characteristics. However, how these distinct subtypes are regulated remains unclear. The investigators hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs within each of the two subtypes.
To prove this, they generated RNA-seq and ChIP-seq data for active (H3K27ac) and repressive histone marks (H3K27me3, H3K9me3) in 24 bladder samples including human primary tumors (13 MIBCs and 2 Non-MIBCs), bladder cancer cellular lines (7) and patient-derived Normal Human Urothelium in proliferation (NHU, n=2). Functional knockdown and knock-out experiments of putative Luminal and Basal-associated master transcription factors were performed in bladder cancer cell lines to validate the findings. Through integrated RNA-sequencing and epigenomic profiling of histone marks, they established the first integrated epigenetic map of bladder cancer and demonstrated the link between subtype and epigenetic control.
The repertoire of activated super-enhancers (SEs) and highlighted Basal, Luminal, and NHU-associated SEs were also found. The investigators described super-enhancer regulated networks of candidate master transcription factors for Luminal and Basal subgroups including FOXA1 and ZBED2 respectively. FOXA1 CRISPR-Cas9 mutation triggered a shift from Luminal to Basal phenotype, confirming its role in Luminal identity regulation, and induced ZBED2 overexpression. In parallel, they showed that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in cancer cells through STAT2 inhibition.
Presented by: Clarice Groeneveld, PhD, Institut Curie, Paris, France
Written by: Roger Li, MD, Urologic Oncologist, Moffitt Cancer Center, during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain