Steroid receptor coactivator-3 as a potential molecular target for cancer therapy

Abstract

Introduction Steroid receptor coactivator-3 (SRC-3), also called amplified-in-breast cancer-1 (AIB1), is an oncogenic coactivator in endocrine and non-endocrine cancers. Functional studies demonstrate SRC-3 promotes numerous aspects of cancer, through its capacity as a coactivator for nuclear hormone receptors and other transcription factors, and via its ability to control multiple growth pathways simultaneously. Targeting SRC-3 with specific inhibitors therefore holds future promise for clinical cancer therapy. Areas covered We discuss critical advances in understanding SRC-3 as a cancer mediator and prospective drug target. We review SRC-3 structure and function and its role in distinct aspects of cancer. In addition, we discuss SRC-3 regulation and degradation. Finally, we comment on a recently discovered SRC-3 small molecular inhibitor. Expert opinion Most targeted chemotherapeutic drugs block only a single cellular pathway. In response, cancers frequently acquire resistance by up-regulating alternative pathways. SRC-3 coordinates multiple signaling networks, suggesting SRC-3 inhibition offers a promising therapeutic strategy. Development of an effective SRC-3 inhibitor faces critical challenges. Better understanding of SRC-3 function and interacting partners, in both the nucleus and cytosol, is required for optimized inhibitor development. Ultimately, blockade of SRC-3 oncogenic function may inhibit multiple cancer-related signaling pathways.

Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3

“…It is important to note that inhibition of SRC-3 is selectively toxic to cancer cells while sparing normal cells (16,17), and prior data showed that knockout of the SRC-3 gene does not influence adult mice life span (37). Consistent with our previously reported SRC-3 SMIs, we did not observe any toxicity of SI-2 up to 500 nM (the highest concentration used) in primary hepatocytes ( Fig.…”

Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer

“…Cyclin E, a cell cycle regulator, 31 and steroid receptor coactivator-3 (SRC-3), a transcriptional coactivator involved in inhibiting apoptotic responses, 32 were significantly increased in Mdm2 SNP309-G/G mice compared with Mdm2 SNP309-T/T mice following AOM treatment (Figure 5d, P = 0.0369 and P = 0.0228, respectively, and Supplementary Figure 4). Together these findings suggest that Mdm2 SNP309-G magnifies AOM-induced changes in ERα and Sp1 expression to alter ERα signaling and influence tumor phenotypes.…”

Steroid receptor coactivator-3 is a pivotal target of gambogic acid in B-cell Non-Hodgkin lymphoma and an inducer of histone H3 deacetylation

“…One previous research also demonstrated GA restrains the growth of xenografted GCB-and ABC-DLBCL cells in nude mice (Shi et al, 2015). In consideration of the therapy-resistant role of overexpressed SRC-3, inhibition of SRC-3 was also required in cancer chemotherapy especially for those chemoresistant cancers (Colo et al, 2007;Tien and Xu, 2012;Yi et al, 2013). GA could be used in combination with conventional chemotherapy to relieve the chemoresistance of cancer.…”

“…SRC-3 has been reported its regulation on histone acetylation through its AD1 domain by interacting with HATs or HDACs (Xu et al, 2009;Yan et al, 2006). And SRC-3 also contains HAT activity (Tien and Xu, 2012). …”

“…The interaction between SRC-3 and histone acetyltransferases (HATs) and histone deacetylases (HDACs) alter the acetylation of histones and influence the transcription of genes (Chang and Wu, 2012). Effective SRC-3 inhibitors have been proposed as a promising therapeutic strategy for these tumors (Tien and Xu, 2012). By now, no clinical data have revealed the overexpression of SRC-3 and its role in NHLs.…”