KATs in cancer: functions and therapies

Abstract

Post-translational acetylation of lysines is most extensively studied in histones, but this modification is also found in many other proteins and is implicated in a wide range of biological processes in both the cell nucleus and the cytoplasm. Like phosphorylation, acetylation patterns and levels are often altered in cancer, therefore small molecule inhibition of enzymes that regulate acetylation and deacetylation offers much potential for inhibiting cancer cell growth, as does disruption of interactions between acetylated residues and 'reader' proteins. For more than a decade now, histone deacetylase inhibitors have been investigated for their ability to increase acetylation and promote expression of tumor suppressor genes. However, emerging evidence suggests that acetylation can also promote cancer, in part by enhancing the functions of oncogenic transcription factors. In this review, we focus on how acetylation of both histone and non-histone proteins may drive cancer, and we will discuss the implications of such changes on how patients are assigned to therapeutic agents. Finally, we will explore what the future holds in the design of small-molecule inhibitors for modulation of levels or functions of acetylation states.

Figure 1. Mechanisms of action of acetylation

A. KATs target both tails and globular domains of all 4 histone proteins. B. KATs acetylate non-histone proteins including transcription factors (TF) as well as metabolic enzymes and other nuclear and cytoplasmic proteins. C. Bromodomain-containing proteins bind to acetyl-lysines on histone tails and on non-histone proteins.

Figure 2. Selected KAT families

Lysine acetyltransferases are classified into different families dependent on their structure. The major families are GNAT, MYST, and CBP/p300. Not all subunits in complexes are represented.

Figure 3. The mechanisms of small molecule inhibitors targeting lysine acetylation

A. Small molecule KAT inhibitors can impair KAT acetyltransferase activity by interfering with AcCoA or substrate binding. The substrates include histone and non-histone proteins, such as p53 and AR. B. Small molecule KAT inhibitors can block interactions between KATs and other proteins, such as beta-catenin and HIF, which would affect transcription of downstream genes. C. Bromodomain inhibitors act as acetyl-lysine mimics that occupy the acetylated lysine binding site in bromodomain-containing proteins.