Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy

Abstract

Coactivators are a diverse group of non-DNA binding proteins that induce structural changes in agonist-bound nuclear receptors (NRs) that are essential for NR-mediated transcriptional activation. Once bound, coactivators function to bridge enhancer binding proteins to the general transcription machinery, as well as to recruit secondary coactivators that modify promoter and enhancer chromatin in a manner permissive for transcriptional activation. In the following review article, we focus on one of the most in-depth studied families of coactivators, the steroid receptor coactivators (SRC) 1, 2, and 3. SRCs are widely implicated in NR-mediated diseases, especially in cancers, with the majority of studies focused on their roles in breast cancer. We highlight the relevant literature supporting the oncogenic activity of SRCs and their future as diagnostic and prognostic indicators. With much interest in the development of selective receptor modulators (SRMs), we focus on how these coactivators regulate the interactions between SRMs and their respective NRs; and, importantly, the influence that coactivators have on the functional output of SRMs. Furthermore, we speculate that coactivator-specific inhibitors could provide powerful, all-encompassing treatments that target multiple modes of oncogenic regulation in cancers resistant to typical anti-endocrine treatments.

Figure 1. SRC-mediated coactivation of NRs

SRC proteins are recruited to hormone bound NRs and bind through their LXXLL motifs, of which they have three. SRCs then recruit multiple secondary coactivator complexes that bind to their three activation domains (ADs). Three examples are shown: histone acetyltransferase, p300/CBP; histone methyltransferases, PRMT1 and CARM1; and chromatin remodeling complex, SWI/SNF. These secondary coactivators modify the chromatin and bridge the NR complex with the general transcription machinery to elicit transcriptional activation. SRCs (steroid receptor coactivators); bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim); S/T (serine/threonine –rich region); NR (nuclear receptor); Ac (acetylation); Me (methylation); HRE (hormone response element); L (LXXLL motifs).

Figure 2. SRC-interacting proteins

SRCs coactivate nuclear receptors (NRs), as well as numerous transcription factors. Once tethered to chromatin via these interactions, SRCs recruit a number of secondary coactivators that interact with its activation domains (ADs). This is a representative list of just some of SRC s interacting proteins, of which SRC-interacting domains have been mapped. Proteins are referenced and adapted from (Kim, 2008) (Yan J., 2008) (Xu et al., 2009) and as mentioned throughout the text.

Figure 3. Multiple cellular factors influence coactivator-NR interactions in the presence of SRMs, affecting SRM functional effects on NR-mediated transcription

Listed are several cellular variables, including NR and coactivator levels and activity, influenced by the differential upregulation of oncogenic signaling pathways, as well as gene-specific promoter contexts that determine whether a SRM will have agonist or antagonist effects. The cartoon demonstrates just some of these potential variables that can impact SRM antagonist/agonist activities and pathways that may be involved. Not all variable are likely to be in play at one time and are cancer, cell- and gene-dependent. SRM (selective receptor modulator); NR (nuclear receptor); HRE (hormone response element; AP-1 (activating protein 1); SRC (steroid receptor coactivator); PKA (protein kinase A); Her2 (human epidermal growth factor 2); P (phosphorylation).