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Review
. 2024 Mar 29;14(1):41.
doi: 10.1186/s13578-024-01222-8.

The multifaceted therapeutic value of targeting steroid receptor coactivator-1 in tumorigenesis

Qiang Chen  1   2 , Peng Guo  3   4 , Yilin Hong  4 , Pingli Mo  4 , Chundong Yu  5
Affiliations
Review

The multifaceted therapeutic value of targeting steroid receptor coactivator-1 in tumorigenesis

Qiang Chen et al. Cell Biosci. .

Abstract

Steroid receptor coactivator-1 (SRC-1, also known as NCOA1) frequently functions as a transcriptional coactivator by directly binding to transcription factors and recruiting to the target gene promoters to promote gene transcription by increasing chromatin accessibility and promoting the formation of transcriptional complexes. In recent decades, various biological and pathological functions of SRC-1 have been reported, especially in the context of tumorigenesis. SRC-1 is a facilitator of the progression of multiple cancers, including breast cancer, prostate cancer, gastrointestinal cancer, neurological cancer, and female genital system cancer. The emerging multiorgan oncogenic role of SRC-1 is still being studied and may not be limited to only steroid hormone-producing tissues. Growing evidence suggests that SRC-1 promotes target gene expression by directly binding to transcription factors, which may constitute a novel coactivation pattern independent of AR or ER. In addition, the antitumour effect of pharmacological inhibition of SRC-1 with agents including various small molecules or naturally active compounds has been reported, but their practical application in clinical cancer therapy is very limited. For this review, we gathered typical evidence on the oncogenic role of SRC-1, highlighted its major collaborators and regulatory genes, and mapped the potential mechanisms by which SRC-1 promotes primary tumour progression.

Keywords: NCOA1; SRC-1; Steroid hormone; Tumour progression.

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Conflict of interest statement

The authors declare that there are no competing interests.

Figures

Fig. 1
Fig. 1
Structures and functional regions of steroid receptor coactivators. (A) The domain structure diagram of steroid receptor coactivators. (B) The functional regions of steroid receptor coactivators. Three homologous SRC proteins (i.e., SRC-1, SRC-2, and SRC-3) have similar molecular weights and protein domains, including bHLH-PAS, NRID AD1, and AD2 domains. The LXXLL motifs located on the NRID are responsible for direct interaction with NRs, and the ADs are primarily responsible for promoting the formation of transcriptional complexes by recruiting secondary coregulatory factors, including p300, CBP, PRMT1, and CARM1
Fig. 2
Fig. 2
The pattern of SRC-1 coactivation. The classical pattern is that SRC-1 serves as a coactivator in a nuclear receptor-dependent, non-DNA binding manner; SRC-1 induces structural changes in nuclear receptors and recruits CBP/P300, PRMT1, and CARM1 to form a transcriptional complex. The emerging model is that SRC-1 directly binds to TFs and co-recruits to the target gene promoter to promote target gene transcription
Fig. 3
Fig. 3
The role of SRC-1 in promoting various biological and pathological processes. SRC-1 has various biological functions and serves as a coactivator for various genes that regulatemetabolic homeostasis, food intake, learning/memory, parturition, and tumorigenesis. SRC-1 is recognized as a coactivator of PPARγ, NR2F6, PGC-1α, and acetyltransferase and participates in the regulation of genes involved in lipid metabolism and adipocyte differentiation. SRC-1 transactivates pyruvate carboxylase by elevating the expression of C/EBPα and regulates both glucose and NAD+/NADH homeostasis, thus participating in the Warburg effect. SRC-1 promotes leptin-mediated STAT3 depolarization and Pomc expression, participating in regulating food intake. In the brain, SRC-1 regulates ER-mediated induction of PR-related gene expression and plays a key role in regulating hippocampal synaptic plasticity and spatial learning and memory. Additionally, SRC-1 promotes parturition by regulating the expression of several genes, including SP-A, partner genes of NF-κb activation, PGF2α, and Il13ra2
Fig. 4
Fig. 4
Potential mechanisms by which SRC-1 promotes breast cancer progression. The transactivation of ER is dependent on leucine-rich motifs, which constitute the ligand-regulated binding site of SRC-1. ER can interact with SRC-1 to modulate the expression of genes central to breast cancer progression. The transcriptional activity of several transcription factors, including HOXC11, PEA3, AP-1, HIF1α, c-FOS, Ets1/2, and STAT1/3, can be increased by SRC-1. Their target genes have various biological activities, such as promotion of tumour proliferation, metastasis, or angiogenesis
Fig. 5
Fig. 5
Potential mechanisms by which SRC-1 promotes prostate cancer progression. SRC-1 participates in androgen-induced AR activation and the regulation of several oncogenes related to prostate cancer progression. IL-6 can modulate AR-independent activation of SRC-1 and promote SRC-1 phosphorylation and nuclear transport by stimulating the MAPK pathway. RORγ can recruit SRC-1 to the AR-ROR response element to promote the transcriptional activity of AR-regulated genes
Fig. 6
Fig. 6
The potential role of SRC-1 in promoting the progression of liver and colorectal cancer. SRC-1 promotes the expression of c-Myc and PCNA by enhancing Wnt/β-catenin signalling, and miR-105-1 negatively regulates SRC-1 by binding to the 3’-UTR of SRC-1 mRNA in HCC. Similarly, SRC-1 promotes CRC progression by promoting the transcription of GLI2 target genes, and miR-4443 inhibits CRC cell proliferation and invasion through the negative regulation of SRC-1
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