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Nuclear Receptor Coactivators: Mechanism and Therapeutic Targeting in Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Andrew Cannon, Christopher Thompson, Rakesh Bhatia, Sushil Kumar
FHL2 is classically a membrane associated protein, but has also been reported to function as a transcriptional coactivator or corepressor of several receptors associated with cancer. In breast cancer, FHL2 overexpression was shown to increase the expression of p21 both in a cell cycle dependent manner and in response to treatment with doxorubicin [123]. FHL2-mediated p21 regulation occurred through the activation of AP-1 transcriptional complex. This upregulation of p21 prevented cell cycle progression through G2/M phase. Cell cycle arrest induction by FHL2 is consistent with an additional study that showed FHL2 is an interaction partner of BRCA1, although this study did not specifically explore the role of FHL2 with respect to DNA repair mechanisms [124]. Despite the role of FHL2 in cell cycle arrest, which suggests a role of FHL2 as a tumor suppressor, its expression in a non-malignant cell line derived from breast tissue showed that FHL2 expression increased the ability of cells to grow in adhesion independent conditions [123]. These findings indicate that FHL2 may have the potential to transform cells or alternatively play a role in tumor initiating cells. In addition to the role of FHL2 in cell cycle arrest in breast cancer cells, studies have suggested other roles for FHL2. With respect to antihormone resistance, Fan et al. showed that long-term culture of breast cancer cells in the absence of estrogens results in sensitization to the apoptosis induced by physiologic concentrations of estrogen [125]. Interestingly, this was shown to be mediated by c-SRC, and inhibition of c-SRC with concomitant estrogen treatment causes cell proliferation and ultimately the emergence of a population of cells that is proliferative in the presence of both tamoxifen and estrogen independent of estrogen receptor [125]. Analysis of this cell population showed that estrogen and tamoxifen treatment resulted in upregulation of several genes including an enrichment of genes associated with the cytoplasmic membrane including FHL2 [126]. The authors claim that this model is reminiscent of antiestrogen resistance in humans, and thus FHL2 is implicated as a putative mediator of this resistance phenotype; however; more detailed studies of the role of FHL2 in this setting are required before firm conclusions can be drawn [126]. Similarly, another study investigated FHL2 in terms of cytoskeletal dynamics. In this study, the partial knockdown of FHL2 reduced breast cancer cell invasion. The study went on to show that expression of full length, but not N- or C-terminal domains of MabP1, inhibited the pro-invasive activity of FHL2 [127]. Ultimately, the pro-invasive activity of FHL2 was tied to its localization at focal adhesions [127]. This finding is similar to those associated with other nuclear receptor coactivators, such as NCOA3, indicating that transcriptional activity may only be a part of the functional role of a nuclear receptor coactivator in physiology and disease.
Androgen receptor, a possible anti-infective therapy target and a potent immune respondent in SARS-CoV-2 spike binding: a computational approach
Published in Expert Review of Anti-infective Therapy, 2023
Ashfaq Ahmad, Zhandaulet Makhmutova, Wenwen Cao, Sidra Majaz, Amr Amin, Yingqiu Xie
Subsequent studies have highlighted the potentials of AR as anti-COVID-19 therapy, whereas anti-androgen treatment has abated SARS-CoV-2 infection in prostate cancer patients or in proposal of vaccine [7–12]. Recently we have demonstrated AR involvement in RBD binding through docking experiments [11], and the potential of AR in SARS-CoV-2 entry has been studied, but whether AR is directly involved in mediating an immune response during COVID-19 disease is debatable. AR contains a ligand binding domain (LBD), DNA binding domain (DBD), and activated functional (AF1, AF2) domains which reflect the domain-mediated roles in transcriptional regulation of target genes [1]. The S1 subunit of the SARS-CoV-2 spike protein induces the angiotensin II type 1 receptor (AT1)-mediated signaling cascade in human epithelial cells, which upon infection can initiate an inflammatory response of the innate immune system. This immune response is brought about by recognition of pathogen-associated molecular patterns (PAMPs) by different pattern recognition receptors (PRRs), e.g, Toll-like, NOD-like, and RIG-I like receptors [2]. Similarly, AR also acts as a ligand-activated transcription factor of the nuclear receptor (NR) super family which interacts with a number of proteins, such as the human NCOA1, NCOA2, NCOA3, NCOA4, and MAGEA11 and associates with the LXXLL and FXXLF motifs via the ligand-binding domain (LBD) [3].
SRC3 deficiency exacerbates lipopolysaccharide-induced acute respiratory distress syndrome in mice
Published in Experimental Lung Research, 2022
Meixia Cui, Shengtong Guo, Ying Cui
Steroid receptor coactivator 3 (SRC3), also known as nuclear receptor coactivator 3 (NCOA3), belongs to the p160 SRC family.11 SRCs regulate gene expression by interacting with nuclear hormone receptors (NRs) and other transcriptional factors. The roles of SCR-3 in development and physiology have been revealed by using SRC3 deficient mice. SRC3 deficiency results in growth retardation and reduced development of mammary gland.12 SRC3 has also been shown to function as oncogene and tumor suppressor.13 The functions of SRC3 in inflammation have been described. SRC3 deficient macrophages produced more inflammatory cytokines after lipopolysaccharides (LPS) stimulation.14 SRC3-/- mice were more sensitive to dextran sodium sulfate (DSS) and developed severe colitis.15 These results suggest that SRC3 should function to suppress inflammation. Until now the precise roles of SRC3 in ARDS remain unknown. In current study, we investigated the role of SRC3 using lipopolysaccharide-induced ARDS mice model.