HDAC5 Expression in Urothelial Carcinoma Cell Lines Inhibits Long-Term Proliferation but Can Promote Epithelial-to-Mesenchymal Transition

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.

Epigenetics of Urological Cancers

“…An important addition to this review is the original article by Buckwalter et al [8] who have systematically investigated the expression of HDACs in cellular and animal model systems of bladder cancer, comparing their results with data from primary tumors. Both articles are complemented by an original investigation addressing the function of HDAC5 [9]. This further supports the conclusion that predominantly class I HDACs, like HDAC1 and HDAC2, drive proliferation and survival of urothelial carcinoma cells [7,10], whereas class IIA enzymes, like HDAC4 and HDAC5, usually impede tumor growth.…”

“…This further supports the conclusion that predominantly class I HDACs, like HDAC1 and HDAC2, drive proliferation and survival of urothelial carcinoma cells [7,10], whereas class IIA enzymes, like HDAC4 and HDAC5, usually impede tumor growth. Intriguingly, however, and in keeping with the ideas outlined by Monteiro-Reis et al [5], overexpression of HDAC5 induced EMT in one urothelial carcinoma cell line [9].…”

METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial–mesenchymal transition of renal tubular cells in diabetic kidney disease

“…As well, knockdown of HDAC5 by siRNA technology in glioma cells suppressed the doxorubicin-induced EMT 18 . Recently, Jaquva et al revealed that HDAC5 overexpression in multiple urothelial carcinoma (UC) cell lines decreased cell proliferation, however in VM-Cub-1 cell line HDAC5 overexpression induced a dramatic EMT change, with the weak effect of HDAC4 on cell phenotypes 19 . Taken together it is suggested that HDAC5 is a promising target to ameliorate diabetic kidney disease via regulating EMT.…”

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

“…Despite the wealth of knowledge regarding these enzymes, we have much to learn. For example, class I HDAC enzymes generally promote tumorigenesis, and class IIA may promote or impede cancer development; however it was only recently discovered that HDAC5 induced anti-proliferative or pro-EMT effects depending on the cell line in which it was overexpressed (154).…”