Histone deacetylases (HDACs) influence diverse cellular processes and may
contribute to tumor development and progression by multiple mechanisms. Class I
HDACs are often overexpressed in cancers contributing to a genome-wide epigenetic state
permitting increased proliferation, and diminished apoptosis and cell differentiation. Class
IIA and IIB isoenzymes may likewise contribute to tumorigenesis as components of specific
intranuclear repressor complexes or regulators of posttranslational protein modifications.
As HDAC inhibitors may counteract these tumorigenic effects several of these
compounds are currently tested in clinical trials.
HDAC inhibitors are also considered for urothelial carcinoma, where novel therapeutic
drugs are urgently required. However, only modest antineoplastic activity has been observed
with isoenzyme-unspecific pan-HDAC inhibitors. Therefore, inhibition of specific
HDAC isoenzymes might be more efficacious and tumor-specific. Here, we systematically
review knowledge on the expression, function and suitability as therapeutic targets
of the 11 classical HDACs in UC. Overall, the class I HDACs HDAC1 and HDAC2 are
the most promising targets for antineoplastic treatment. In contrast, targeting HDAC8 and
HDAC6 is likely to be of minor relevance in urothelial carcinoma. Class IIA HDACs like
HDAC4 require further study, since their downregulation rather than upregulation could
be involved in urothelial carcinoma pathogenesis.