Dual role of GRHL3 in bladder carcinogenesis is associated with histological subtypes

Grainyhead-like transcription factor 3 (GRHL3) is known to affect cancer development depending on subtypes in various entities. Here, we analyzed the subtype-specific role of GRHL3 in bladder carcinogenesis comparing common urothelial carcinoma (UC) with squamous bladder cancers (sq-BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role as well as its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3 overexpressing EJ28 and SCaBER in vitro models revealed a tumor suppressive function in squamous and a oncogenic role in the urothelial cancer cells affecting cell migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype specific GRHL3 regulated expression networks coined by enrichment of genes involved in integrin mediated pathways. In SCaBER loss of RhoA GTPase activity was demonstrated associated with co-regulation of EIF4E3, a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer. Overall design: To investigate the function of GRHL3 in bladder carcinogenesis comparing different histological subtypes, we generated GRHL3 overexpressing single cell clone models in urothelial cell line EJ28 and squamous-like cell line SCaBER. We used mock clones as references with low (EJ28) and moderate (SCaBER) endogenous GRHL3 expression.