Histone deacetylase inhibitors and epigenetic modifications as a novel strategy in renal cell carcinoma

Abstract

Recent investigations of renal cell carcinoma (RCC) have revealed several epigenetic modifications, as well as alterations in the genes and enzymes that regulate these changes. Preclinical models have revealed that histone gene modifiers and epigenetic alterations may play a critical role in RCC tumorigenesis. Specific changes in DNA methylation and mutations of histone modifiers have been identified and may be associated with an aggressive phenotype. In addition, the potential of reversing the effects of these enzymes and hence reversing the cellular epigenetic landscape to a "normal phenotype" have led to an increasing interest in developing targeted chromatin remodeling agents. However, the translation of the understanding of these changes to the clinic for the treatment of RCC has posed significant challenges, partly due to tumor heterogeneity. This review describes the aberrant histone and DNA alterations recently reported in RCC and highlights the potential targeted chromatin remodeling therapies in the management of this disease.

Figure 1. Summary of histone modifications and enzymes involved

The nucleosome structure consists of the octamer core (H2A, H2B, H3, and H4) with the linker histone (H1). Histone tails can be modified through phosphorylation, acetylation, ubiquitination and methylation. DNA, however, can be only acetylated or methylated at different sites including promoter regions and CpG islands. Enzymes causing above mentioned modifications are Histone deacetylases (HDACs), Histone acetyl transferases (HATs), Histone methyl transferases (HMTs) and Histone demethylases (HDMTs). DNA can be methylated by a group of enzymes known as DNA methyl transferases and deacetylated by class II HDACs.

Figure 2. Examples of HDAC inhibitor activity and clinical studies in RCC

Summary of the different studies conducted in vitro, in vivo and clinical trials combining HDACs with other agents. Upper panel: genes and pathways affected by HDAC inhibitors. Lower panels: combination clinical trials with HDAC inhibitors.