Abstract
Class I histone deacetylases (HDACs) generally promote cell proliferation and tumorigenesis, whereas class IIA HDACs like HDAC4 and HDAC5 may promote or impede cancer development in a tissue-dependent manner. In urothelial carcinoma (UC), HDAC5 is often downregulated. Accordingly, HDAC5 was weakly expressed in UC cell lines suggesting a possible tumor-suppressive function. We therefore characterized the effects of stable HDAC5 expression in four UC cell lines (RT112, VM-Cub-1, SW1710 and UM-UC-3) with different phenotypes reflecting the heterogeneity of UC, by assessing proliferation, clonogenicity and migration ability. Further, we detailed changes in the proteome and transcriptome by immunoblotting, mass spectrometry and RNA sequencing analysis. We observed that HDAC5 overexpression in general decreased cell proliferation, but in one cell line (VM-Cub-1) induced a dramatic change from an epitheloid to a mesenchymal phenotype, i.e., epithelial-mesenchymal transition (EMT). These phenotypical changes were confirmed by comprehensive proteomics and transcriptomics analyses. In contrast to HDAC5, overexpression of HDAC4 exerted only weak effects on cell proliferation and phenotypes. We conclude that overexpression of HDAC5 may generally decrease proliferation in UC, but, intriguingly, may induce EMT on its own in certain circumstances.
Highlights
Histone deacetylases (HDACs) remove acetyl groups from histone or non-histone proteins and regulate gene expression as components of multiprotein repressor complexes [1,2,3,4]
Class IIA HDACs may be involved in cancer development, but, in contrast to class I HDACs, they may promote or impede cancer development depending on the tissue [4,7]
Expression of HDAC4 and HDAC7 was variable among the cell lines
Summary
Histone deacetylases (HDACs) remove acetyl groups from histone or non-histone proteins and regulate gene expression as components of multiprotein repressor complexes [1,2,3,4]. Class IIB enzymes, especially HDAC6, appear to be important for cellular stress responses. The function of the class IIA enzymes, HDACs 4, 5 and 7, in cancer is less well understood. Different from class I HDACs, they do not appear to contribute substantially to global histone acetylation and may have limited catalytic activity. Rather, they interact with transcription factors and other chromatin proteins, including class I HDACs, to repress specific genes. Expression and functions of class IIA HDACs are more tissue-specific. Class IIA HDACs may be involved in cancer development, but, in contrast to class I HDACs, they may promote or impede cancer development depending on the tissue [4,7]
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