Bcakground: Programmed death-ligand 1 (PD-L1), one of the immunosuppressive molecules, overexpresses in multiple cancers and is critical for their immune escape. We previously showed that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability; however, the role of SRC-1 in CRC immune escape is unclear. Herein, we aim to explore the underlying mechanisms of SRC-1-mediated immune escape in CRC and to find new strategies for treating CRC.Methods: We used CRC cell lines, murine models (subcutaneous grafts and AOM/DSS-induced tumor model), plus CRC patient specimens to delineate the molecular mechanisms by which SRC-1 promotes CRC immune escape. In addition, we used the SRC-1 inhibitor bufalin to further investigate whether targeting SRC-1 could enhance the efficacy of immunotherapy.Findings: We demonstrated that SRC-1 was positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibited PD-L1 expression in both human and murine CRC cells and retarded murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration and antitumor activity of effector CD8+ T cells. Genetic ablation of SRC-1 in mice also decreased PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models.Interpretation: We identified a crucial role of SRC-1 in facilitating CRC immune escape and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment.Funding: This study was supported by the National Natural Science Foundation of China and Natural Science Foundation of Ningbo.Declaration of Interest: The authors have declared that no conflict of interest exists.Ethical Approval: All animal experiments were conducted under protocols approved by the Laboratory Animal Center of Xiamen University. For experiments using human specimens, all specimens were anonymously coded in accordance with the Declaration of Helsinki. The study protocol that conformed to the ethical guidelines was approved by the Medical Ethics Committee at school of medicine, Xiamen University.
Steroid receptor coactivator 3 (SRC-3) is a multifunctional protein that plays an important role in malignancy of several cancers and in regulation of bacterial LPS-induced inflammation. However, the involvement of SRC-3 in allergic response remains unclear. Herein we used passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA) mouse models to assess the role of SRC-3 in allergic response.SRC-3-deficient mice exhibited more severe allergic response as demonstrated by a significant drop in body temperature and a delayed recovery period compared to wild-type mice in PSA mouse model, whereas no significant difference was observed between two kinds of mice in PCA mouse models. Mast cells play a pivotal role in IgE-mediated allergic response. Antigen-induced aggregation of IgE receptor (FcϵRI) on the surface of mast cell activates a cascade of signaling events leading to the degranulation and cytokine production in mast cells. SRC-3-deficient bone marrow derived mast cells (BMMCs) developed normally but secreted more proinflammatory cytokines such as TNF-α and IL-6 than wild-type cells after antigen stimulation, whereas there was no significant difference in degranulation between two kinds of mast cells. Further studies showed that SRC-3 inhibited the activation of nuclear factor NF-κB pathway and MAPKs including extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 in antigen-stimulated mast cells.Our data demonstrate that SRC-3 suppresses cytokine production in antigen-stimulated mast cells as well as PSA in mice at least in part through inhibiting NF-κB and MAPK signaling pathways. Therefore, SRC-3 plays a protective role in PSA and it may become a drug target for anaphylactic diseases.
Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors such as the estrogen receptor and the androgen receptor and several other transcription factors to enhance their effects on target gene expression. SRC-3 plays important roles in many developmental, physiological, and pathologic events, including body growth, mammary gland development, energy homeostasis, inflammatory regulation, and cancer initiation and progression. SRC-3 has been suggested to be involved in host defense against bacterial pathogens. In this review, we summarize the roles of SRC-3 in host defense against peritoneal and enteric bacterial infection and discuss the potential clinical implications.
Abstract Programmed death-ligand 1 (PD-L1), one of the immunosuppressive molecules, overexpresses in multiple cancers and is critical for their immune escape. We previously showed that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability; however, the role of SRC-1 in CRC immune escape is unclear. Here, we demonstrated that SRC-1 was positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibited PD-L1 expression in both human and murine CRC cells and retarded murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration and antitumor activity of effector CD8+ T cells. Genetic ablation of SRC-1 in mice also decreased PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, our findings highlight a crucial role of SRC-1 in facilitating CRC immune escape and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment. Citation Format: Yilin Hong, Qiang Chen, Zinan Wang, Yong Zhang, Bei Li, Xu Kong, Pingli Mo, Nengming Xiao, Jianming Xu, Yunbin Ye, Chundong Yu. Nuclear receptor coactivator SRC-1 promotes colorectal cancer immune escape by enhancing PD-L1 transcription and protein stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1688.
Ethnopharmacological relevanceJian-Pi-Yi-Shen formula (JPYS) has been demonstrated to be an effective herbal therapy against renal injury and clinically applied to ameliorate chronic kidney disease (CKD) and CKD-associated anemia. Increasing evidence supports the link between renal fibrosis and anemia in CKD. Nevertheless, research on the mechanism of JPYS in ameliorating renal anemia (RA) by suppressing renal fibrosis remains to be clarified.Aim of the studyOur study here was carried out to investigate the mechanism of JPYS in protecting against renal fibrosis-induced RA.Materials and methodsAn adenine-induced anemia model in rats with CKD was established, and samples taken from three different time points were analyzed. Biochemical analysis was employed to detect kidney function and hematological parameters, and Masson staining was used to evaluate renal fibrosis of rats. Western blot and immunohistochemistry were utilized to assist in further pharmacological evaluations, which collectively encompassed the expressions of fibrotic markers, erythropoietin (EPO) and hypoxia inducible factor-2α (HIF-2α) in the kidneys of rats. Subsequently, transcriptomic analysis was conducted to disclose the possible mechanisms of JPYS in treating renal fibrosis-induced RA. Finally, the expression levels of key targets were analyzed and validated by using western blot and enzyme-linked immunosorbent assay (ELISA).ResultsJPYS treatment improved kidney function and renal fibrosis, and enhanced hematological parameters. Moreover, JPYS treatment recovered the increased expression levels of fibrotic markers and declined EPO with time dependence. Further investigation indicated JPYS treatment stimulated the translocation of HIF-2α into nucleus within renal interstitium and thus promoted the expression of EPO. Transcriptomic analysis disclosed that activations of both nuclear factor kappa B (NF-κB) and transforming growth factor-β (TGF-β)/Smad pathways were closely associated with renal fibrosis-induced RA. Ultimately, experimental validation results presented that the expressions of target proteins from the above-mentioned two pathways in the kidneys were decreased significantly after JPYS treatment.ConclusionJPYS can ameliorate renal fibrosis-induced RA in CKD rats, and this effect may be associated with inhibition of NF-κB and TGF-β/Smad signaling pathways. Our findings highlight that JPYS is a favorable therapeutic strategy for renal fibrosis-induced RA.
Background: As a histone demethylase, JMJD2D can enhance gene expression by specifically demethylating H3K9me2/3 and plays an important role in promoting colorectal cancer progression. However, its role in liver cancer remains unclear. Methods: The expression of JMJD2D was examined in human liver cancer specimens and non-tumorous liver tissues by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in liver cancer cells using small hairpin RNAs, and cells were analyzed with Western blot, real-time PCR, cell viability, colony formation, and flow cytometry assays. Cells were also grown as tumor xenografts in nude mice, and the tumor cell proliferation and apoptosis were measured by immunohistochemical analysis. The relationship between JMJD2D and p53 was studied by co-immunoprecipitation, chromatin immunoprecipitation, and electric mobility shift assay. Wild-type and JMJD2D-knockout mice were intraperitoneally injected with diethylnitrosamine (DEN) to induce liver tumors and the liver cancer initiation and progression were investigated. Results: JMJD2D was frequently upregulated in human liver cancer specimens compared with non-tumorous liver tissues. The overall survival of liver cancer patients with high JMJD2D expression was significantly decreased compared to that with low JMJD2D expression. JMJD2D knockdown reduced liver cancer cell proliferation and xenograft tumor growth, sensitized cells to chemotherapeutic drug-induced apoptosis, and increased the expression of cell cycle inhibitor p21 and pro-apoptosis gene PUMA. Genetically, JMJD2D deficiency protected mice against DEN-induced liver cancer initiation and progression. Knockout of tumor suppressor p53 significantly reduced the effects of JMJD2D knockdown on cell proliferation, apoptosis, and the expression of p21 and PUMA, suggesting that JMJD2D regulates liver cancer cell functions in part through inhibiting p53 signaling pathway. Mechanistically, JMJD2D directly interacted with p53 and inhibited p53 recruitment to the p21 and PUMA promoters in a demethylation activity-independent manner, implicating a demethylase-independent function of JMJD2D as a novel p53 antagonist. In addition, JMJD2D could activate Wnt/β-catenin signaling to promote liver cancer cell proliferation. Conclusion: Our study demonstrates that JMJD2D can antagonize the tumor suppressor p53 and activate an oncogenic signaling pathway (such as Wnt/β-catenin signaling pathway) simultaneously to promote liver cancer initiation and progression, suggesting that JMJD2D may serve as a novel target for liver cancer treatment.
The histone demethylase Jumonji domain containing 1A (JMJD1A) is overexpressed in multiple tumors and promotes cancer progression. JMJD1A has been shown to promote colorectal cancer (CRC) progression, but its molecular role in CRC is unclear. Here, we report that JMJD1A is overexpressed in CRC specimens and that its expression is positively correlated with that of proliferating cell nuclear antigen (PCNA). JMJD1A knockdown decreased the expression of proliferative genes such as c-Myc, cyclin D1, and PCNA, suppressed CRC cell proliferation, arrested cell cycle progression, and reduced xenograft tumorigenesis. Furthermore, JMJD1A knockdown inhibited CRC cell migration, invasion, and lung metastasis by decreasing matrix metallopeptidase 9 (MMP9) expression and enzymatic activity. Moreover, bioinformatics analysis of GEO profile datasets revealed that JMJD1A expression in human CRC specimens is positively correlated with the expression of Wnt/β-catenin target genes, including c-Myc, cyclin D1, and MMP9. Mechanistically, JMJD1A enhanced Wnt/β-catenin signaling by promoting β-catenin expression and interacting with β-catenin to enhance its transactivation. JMJD1A removed the methyl groups of H3K9me2 at the promoters of c-Myc and MMP9 genes. In contrast, the JMJD1AH1120Y variant, which lacked demethylase activity, did not demethylate H3K9me2 at these promoters, failed to assist β-catenin to induce the expression of Wnt/β-catenin target genes, and failed to promote CRC progression. These findings suggest that JMJD1A's demethylase activity is required for Wnt/β-catenin activation. Of note, high JMJD1A levels in CRC specimens predicted poor cancer outcomes. In summary, JMJD1A promotes CRC progression by enhancing Wnt/β-catenin signaling, implicating JMJD1A as a potential molecular target for CRC management.
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