Selective antagonism of cJun for cancer therapy

Abstract

The activator protein-1 (AP-1) family of transcription factors modulate a diverse range of cellular signalling pathways into outputs which can be oncogenic or anti-oncogenic. The transcription of relevant genes is controlled by the cellular context, and in particular by the dimeric composition of AP-1. Here, we describe the evidence linking cJun in particular to a range of cancers. This includes correlative studies of protein levels in patient tumour samples and mechanistic understanding of the role of cJun in cancer cell models. This develops an understanding of cJun as a focal point of cancer-altered signalling which has the potential for therapeutic antagonism. Significant work has produced a range of small molecules and peptides which have been summarised here and categorised according to the binding surface they target within the cJun-DNA complex. We highlight the importance of selectively targeting a single AP-1 family member to antagonise known oncogenic function and avoid antagonism of anti-oncogenic function.

Keywords: Activator Protein-1; basic leucine zipper; c-Jun; cancer; peptides; protein-protein interaction; transcriptional regulator.

Fig. 1

Sequence and structure of AP-1 proteins. a Crystal structure of the cFos-cJun heterodimer binding to DNA (PDB code: 1FOS); b Schematic illustrating the domain structures of AP-1 proteins, adapted from Ref [51]; c Sequence alignment of the bZIP domains from selected AP-1 proteins

Fig. 2

Overview of selected cJun signalling pathways. In general, a stimulus is passed through a MAPK cascade (sometimes via a small G protein) to alter the activity of transcription factors which act upon the cJun gene; this changes expression of target genes by the formation of an AP-1 dimer which binds to TRE DNA. Exemplary pathways have been shown which are indicative of the general signalling through which a stimulus leads to cJun mediated cellular changes. The pathways are therefore not necessarily complete as well as some of these activations occurring indirectly. Created with Biorender.com

Fig. 3

Schematic of cJun binding interfaces and molecules that target them. The cJun-DNA interaction can be antagonised by binding to the TRE site on DNA (MLN44 [129], SR11302 [135]), the cJun DBD (T-5224) [51], the cJun LZ (anti-Jun and anti-Fos SZ [144], FosU_isCan [125]) or the full cJun bZIP domain (A-Fos [148])

Fig. 4

Overview of the potential interactions of a cJun antagonist. This highlights some potential competitive interactions which the antagonist must overcome in order to selectively bind to the cJun target; outcompeting both homodimerisation and interactions with off target components