Abstract
Epigenetic aberrations are prominent in bladder cancer (BC) and contribute to disease pathogenesis. We characterized histone deacetylase (HDAC) expression, a family of deacetylation enzymes, in both in vitro and in vivo BC model systems and analyzed expression data from The Cancer Genome Atlas (TCGA). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis was used to determine the expression status of Class I and II HDACs in ten human BC cell lines, while qRT-PCR was used to determine HDAC expression in 24 human tumor specimens. The TCGA cohort consists of 408 muscle invasive BC (MIBC) clinical samples and analysis of this data set identified expression of HDAC4 and -9 as being associated with basal–squamous disease. These findings agree with qRT-PCR results identifying increased expression of HDAC4, -7, and -9 in basal BC cell lines (p < 0.05; Kruskal–Wallis test) and in clinical specimens with invasive bladder cancer (not statistically significant). We also observed increased expression in Hdac4, -7, and -9 in commonly used BC mouse models. Here, we identify suitable preclinical model systems for the study of HDACs, and show increased expression of Class IIa HDACs, specifically HDAC4 and HDAC9, in basal BC cell lines and in invasive clinical specimens. These results suggest this class of HDACs may be best suited for targeted inhibition in patients with basal BC.
Highlights
It is estimated that 80,470 cases of bladder cancer (BC) will be diagnosed in 2019 [1]
Perhaps the most interesting observation of the genetic alterations of histone deacetylase (HDAC) in these ten BC cell lines is HDAC5, the only HDAC to be mutated in more than one cell line. These results indicate that genomic alterations associated with genes encoding various HDAC members play a potential role in regulating the expression and/or function of these enzymes
Class I HDACs consist of HDAC1, -2, -3, and -8
Summary
It is estimated that 80,470 cases of bladder cancer (BC) will be diagnosed in 2019 [1]. FOXA1 expression is inversely correlated with the expression of HDAC4, -5, and -9 (−0.30, −0.27, and −0.37 respectively; q < 0.00001) These observations are interesting because HDAC4, -5, and -9 are members of class IIa HDACs which we observed as being overexpressed in BC cell lines with a basal or non-type molecular subtype (Figures 2 and 3) as well as in basal–squamous BC clinical samples (Figure 4). Decreased FOXA1 expression correlated with a basal molecular subtype in BC cell lines and in patients with basal–squamous disease These observations suggest class IIa HDACs may play a role in regulating FOXA1 expression in basal BC. We observed increased expression that was primarily cytoplasmic for Hdac and -9 (Figure 6s,t) These results indicate combined expression of SV40T and oncogenic Hras in mouse urothelium alters Hdac and -9 expression and localization which may contribute to the development of CIS in this model.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call