Nonhistone protein acetylation as cancer therapy targets

Abstract

Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of histone acetylation in the modification of chromatin structure and dynamics, and thereby gene transcription regulation, has been well recognized. A steadily growing number of nonhistone proteins have been identified as acetylation targets and reversible lysine acetylation in these proteins plays an important role(s) in the regulation of mRNA stability, protein localization and degradation, and protein-protein and protein-DNA interactions. The recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation, differentiation and apoptosis. Many nonhistone proteins targeted by acetylation are the products of oncogenes or tumor-suppressor genes and are directly involved in tumorigenesis, tumor progression and metastasis. Aberrant activity of HDACs has been documented in several types of cancers and HDAC inhibitors (HDACi) have been employed for therapeutic purposes. Here we review the published literature in this field and provide updated information on the regulation and function of nonhistone protein acetylation. While concentrating on the molecular mechanism and pathways involved in the addition and removal of the acetyl moiety, therapeutic modalities of HDACi are also discussed.

Figure 1. Acetylation regulates p53 function

p53 loosely binds to the repressed, tightly packed chromatin. A cascade of events initiated with the phosphorylation of p53, followed by recruitment of acetyltransferases and methyltransferases takes place, leading to p53 acetylation. Acetylated p53 binds tightly to the acetylated and methylated chromatins. The overall effects are relaxation of chromatin and transcription activation. Deacetylation of p53 and nucleosomal histones by HDAC-1 or SirT2 reverses the process and leads to chromatin tightening and transcription repression. Ac: Acetyl group; HAT: Histone acetyltransferase; HDAC: Histone deacetylase.

Figure 2. Histone deacetylase recruitment and transcription repression

Histone octamers are represented by circles and the DNA is shown in black lines. HDAC is recruited to gene promoters by nonhistone proteins including methylated DNA-binding protein MeCP2, ER, methyl transferases (DNMT) and transcription factors (E2F, Rb). HDAC removes the acetyl group from nonhistone as well as histone proteins, which leads to chromatin conformational change and transcription repression of tumor-suppression genes. The loss of tumor-suppressor gene products contributes to the block of cell differentiation, uncontrolled cell proliferation, interrupted apoptosis and, ultimately, tumor formation. ER: Estrogen receptor; HDAC: Histone deacetylase; Rb: Retinoblastoma protein.