H3K27me3 modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE235907 | GEO | 2023/11/22
REPOSITORIES: GEO
Similar Datasets
Project description:Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer, but the underlying mechanisms are still not fully understood. Our study revealed a close association between H3K27me3 and cyclophosphamide (CTX)-induced ovarian damage, especially in granulosa cells.
2023-11-22 | GSE236296 | GEO
Project description:Abnormal granulosa cells (GCs) death contributes to cyclophosphamide (CTX) -induced primary ovarian insufficiency (POI). To investigate the contribution of GCs in POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) are enriched in ferroptosis-related pathway, which is correlated with the upregulated Heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed that iron overload and disrupting ROS, including cytoROS, mtROS and lipROS homeostasis by HO-1 upregultion could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies the role of ROS in CTX-induced ferroptosis and highlighted the effect of HO-1 modulators of improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.
2023-10-30 | GSE243720 | GEO
Project description:The role of cyclophosphamide (CTX) as a first-line chemotherapy drug in the reproductive health of young women with cancer has been controversial, especially considered to increase the risk of premature ovarian failure (POF). Therefore, in this study, c57bl/6 mice were treated by a single intraperitoneal injection of CTX.Our study suggests that CTX mainly regulates ovarian development by activate transcription factors, while reduce cholesterol production and lipid metabolism.
2020-01-01 | GSE128240 | GEO
Project description:Certain anticancer drugs, particularly cyclophosphamide (CTX), were shown to enhance the antitumor efficacy of immunotherapy through different immunomodulatory mechanisms. A better understanding of the cellular and molecular basis of CTX-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Transcript profiling and flow cytometry were used to explore CTX immune-enhancing activity in patients with hematologic malignancies. A single high-dose treatment quickly (1-2 days) induced an extensive transcriptional modulation in peripheral blood mononuclear cells, leading to the reduction of cell cycle and biosynthetic/metabolic processes and to the augmentation of transcripts related to DNA damage and cell death (p53 signaling pathway, CDKN1A, CCND3, BAX, BBC3, BID, DDB2, SESN2), of scavenger receptors involved in the recognition of death (MARCO, CD68, CD163L1, SCARB2), of antigen processing/presentation mediators (CIITA, CTSC, CTSL1, CTSZ, GLA, GAA, TPP1, NEU1, SLC11A1, LAMP-2), of T cell activation markers (CD69, OX40) and, noticeably, of a type I interferon (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, the plasma levels of IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, BAFF) were increased by treatment. Accordingly, CTX preconditioning induced both monocyte and lymphocyte activation, leading to the expansion of CD14+CD16+ monocytes, of HLA-DR+, IL8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, IL8RA+ lymphocytes. Altogether, these data define for the first time the immunomodulatory factors induced by CTX in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated to its cytotoxic action on blood cells, through p53 and IFN-I-related mechanisms. Four-condition experiment, Untreated (10 Biological replicates) - Cyclophosphamide-treated 1 day (10 Biological replicates) - Cyclophosphamide-treated 2 days (8 Biological replicates) - Cyclophosphamide-treated 5 days (5 Biological replicates). Each sample labeled with Cy5 and co-hybridized with Cy3-labeled M-bM-^@M-^\referenceM-bM-^@M-^] aRNA. One replicate per array.
2013-09-02 | E-GEOD-39324 | biostudies-arrayexpress
Project description:H3K27me3 modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury
| PRJNA988016 | ENA
Project description:Primary ovarian insufficiency (POI) is an early decline in ovarian function that leads to infertility. Conventional treatments for chemotherapy-induced POI are unsatisfactory. Mesenchymal stem cells (MSCs) have emerged as a therapeutic option, but the impact of estrogen niche-respond MSC secretome on ovarian regeneration and circadian rhythm remains unknown. This study revealed that the secretome of ER+pcMSCs (conditioned medium [CM] and E2-CM, respectively) significantly reduced the CTX-induced defects in ovarian folliculogenesis and circadian rhythm. The CM/E2-CM also reduced granulosa cell apoptosis and rescued angiogenesis in POI ovarian tissues. E2-CM presented a better effect than the CM. Cytokine array analysis showed a significant increase in cytokine/growth factors associated with immunomodulation and angiogenesis (including angiogenin). Neutralizing angiogenin in the CM/E2-CM significantly decreased its ability to promote HUVEC tube formation in vitro. Importantly, the ER+pcMSC secretome restored the CTX-induced circadian rhythm defects, including the expression of both the genes and proteins associated with ovarian circadian clock (such as Rora, E4bp4, Rev-erbα, and Dbp) and the locomotor activity. Further exosomal miRNA analysis showed the involved miRNAs in targeting the genes associated with POI rescue (Pten and Pdcd4), Caspase-3, estrogen synthesis (Cyp19a1), and importantly the ovarian clock regulation (E4bp4, Rev-erbα and Rev-erbβ).
2024-10-23 | GSE247568 | GEO
Project description:H3K27me3 modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury [CUT&Tag]
| PRJNA989644 | ENA
Project description:Certain anticancer drugs, particularly cyclophosphamide (CTX), were shown to enhance the antitumor efficacy of immunotherapy through different immunomodulatory mechanisms. A better understanding of the cellular and molecular basis of CTX-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Transcript profiling and flow cytometry were used to explore CTX immune-enhancing activity in patients with hematologic malignancies. A single high-dose treatment quickly (1-2 days) induced an extensive transcriptional modulation in peripheral blood mononuclear cells, leading to the reduction of cell cycle and biosynthetic/metabolic processes and to the augmentation of transcripts related to DNA damage and cell death (p53 signaling pathway, CDKN1A, CCND3, BAX, BBC3, BID, DDB2, SESN2), of scavenger receptors involved in the recognition of death (MARCO, CD68, CD163L1, SCARB2), of antigen processing/presentation mediators (CIITA, CTSC, CTSL1, CTSZ, GLA, GAA, TPP1, NEU1, SLC11A1, LAMP-2), of T cell activation markers (CD69, OX40) and, noticeably, of a type I interferon (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, the plasma levels of IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, BAFF) were increased by treatment. Accordingly, CTX preconditioning induced both monocyte and lymphocyte activation, leading to the expansion of CD14+CD16+ monocytes, of HLA-DR+, IL8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, IL8RA+ lymphocytes. Altogether, these data define for the first time the immunomodulatory factors induced by CTX in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated to its cytotoxic action on blood cells, through p53 and IFN-I-related mechanisms.
2013-09-02 | GSE39324 | GEO
Project description:Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer; however, the underlying mechanisms are still not fully understood. Our study has revealed a close association between epigenetic regulation and cyclophosphamide (CTX)-induced ovarian damage. Specifically, CTX and its active metabolite 4-hydroperoxy cyclophosphamide (4-HC) were found to increase the apoptosis of granulosa cells (GCs) by reducing EZH2 and H3K27me3 levels, both in vivo and in vitro. Furthermore, RNA-seq and CUT&Tag analyses revealed that the loss of H3K27me3 peaks on promoters led to the overactivation of genes associated with transcriptional regulation and apoptosis, indicating that stable H3K27me3 status could help to provide a safeguard against CTX-induced ovarian damage. Administration of the H3K27me3-demethylase inhibitor, GSK-J4, prior to CTX treatment could partially mitigate GC apoptosis by reversing the reduction of H3K27me3 and the aberrant upregulation of specific genes involved in transcriptional regulation and apoptosis. GSK-J4 could thus potentially be a protective agent for female fertility when undergoing chemotherapy. The results provide new insights into the mechanisms for chemotherapy injury and future clinical interventions for fertility preservation.
| S-EPMC10646043 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) therapy is a standard treatment option for many malignancies, but it is only effective in a subset of patients. Combination strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoidinduced TNFR-related (GITR) protein with agonist antibodies has shown efficacy in preclinical models, but GITR engagement does not control growth of advanced poorly immunogenic murine tumors such as B16 melanoma and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) preferentially depletes regulatory T cells (Tregs) and expands tumor-specific effector T cells (Teffs) via homeostatic proliferation. Additionally, CTX directly induces tumor cell death, thereby releasing antigen to prime Teffs in a lymphopenic environment where there are fewer Tregs. GITR agonism has a net inhibitory effect on Tregs and yet activates Teff. We therefore hypothesized that CTX treatment prior to GITR agonism would promote potent anti-tumor immunity. Here we show that the combination of CTX and GITR agonism robustly controls tumor growth in several clinically relevant mouse models. Mechanistically, we show that the combination therapy causes tumor cell death, clonal expansion of highly active and terminally differentiated CD8+ T cells, and depletion of regulatory T cells by AICD. Control of tumor growth was also associated with the presence of an expanded population of highly activated tumor-infiltrating oligoclonal CD8+ T cells that lead to a global contracted TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemo-immunotherapeutic approach that warrants further clinical investigation.
2021-11-18 | GSE182292 | GEO