HSF1 promotes proliferation and chemoresistance in diffuse large B-cell lymphoma by enhancing cell cycle and DNA repair
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PROVIDER: PRJNA1256473 | ENA |
REPOSITORIES: ENA
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Project description:To further elucidate the mechanism of HSF1-mediated transcriptional regulation in diffuse large B-cell lymphoma, we conducted transcriptomic sequencing on SU-DHL-2 and SU-DHL-6 cells treated with or without DTHIB (8 μM).
2025-07-23 | GSE295838 | GEO
Project description:SOX9 was identified as a prognostic biomarker particularly in IGH-BCL2 translocated germinal center B cell (GCB) subtypes of the diffuse large B cell lymphoma (DLBCL) and plays a vital role in lymphomagenesis. However, the molecular mechanism that modulating the aberrant expression of SOX9 in this DLBCL subset remains unknown. We have demonstrated that SOX9 enhanced IGH-BCL2 positive DLBCL subset resistance to either chemotherapy or BCL2 inhibitor. Moreover, we found that inhibition of BCL2 downregulates SOX9 in IGH-BCL2 positive DLBCL subset. We further identified that IRF4 is a key regulator to mediate BCL2 induced SOX9 expression, alongside with the chip-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promote IRF4 entry into the nucleus by enhancing its protein stability, via downregulating of proteosome ubiquitination process, and, therefore, enforce SOX9-mediated phenotypes. Finally, we showed in DLBCL cell lines and xenografted mice model that in vivo inhibition of IRF4 with hIRF4 antisense oligonucleotide (ASO) repressed lymphomagenesis and DLBCL chemoresistance. Altogether, our data support the conclusion that IRF4 plays an essential role in BCL2 induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapse and refractory DLBCL in the future.
2024-09-30 | GSE278092 | GEO
Project description:Diverse cellular insults converge on activation of the heat shock factor 1 (HSF1), which regulates the proteotoxic stress response to maintain protein homoeostasis. HSF1 regulates numerous gene programmes beyond the proteotoxic stress response in a cell-type- and context-specific manner to promote malignancy. However, the role(s) of HSF1 in immune populations of the tumour microenvironment remain elusive. Here, we leverage an in vivo model of HSF1 activation and single-cell transcriptomic tumour profiling to show that augmented HSF1 activity in natural killer (NK) cells impairs cytotoxicity, cytokine production, and subsequent anti-tumour immunity. Mechanistically, HSF1 directly binds and regulates the expression of key mediators of NK cell effector function. This work demonstrates that HSF1 regulates the immune response under the stress conditions of the tumour microenvironment. These findings have important implications for enhancing the efficacy of adoptive NK cell therapies and for designing combinatorial strategies including modulators of NK cell-mediated tumour killing. This SuperSeries is composed of the SubSeries listed below.
2021-02-26 | GSE167552 | GEO
Project description:Upon heat shock, Hsf1 protein is extensively phosphorylated, however, this modification is inhibited by an hsf1-bal mutation. To get genome-wide effect of the hyperphosphorylation on Hsf1-regulated transcription, the heat-induced gene expression profiles in HSF1 and hsf1-bal cells were compared. Keywords: stress response
2005-09-27 | GSE3361 | GEO
Project description:Heat shock factor 1 (HSF1) is a key stress-protective transcription factor that is exploited by various cancers to promote cancer cell survival, therapy resistance, and metastasis. Metastatic castration-resistant prostate cancer (mCRPC) is the leading cause of cancer-related death in men worldwide, and mCRPC progression is associated with increased dependence on HSF1. However, mechanisms underlying HSF1 stabilization and persistent activation in metastatic malignancies remain unclear. Here we show that the HSF1-driven transcriptional program and its genome occupancy in mCRPC cells are distinct from those of CRPC cells. HSF1 is highly activated and required for the metastatic potential of mCRPC cells. Moreover, we report DBC1 as a critical regulator of HSF1 stability and activity in mCRPC cells. DBC1 is required for genome-wide chromatin occupancy and target gene expression of HSF1. Mechanistically, DBC1 enhances DYRK2/PKA-mediated HSF1 phosphorylation at S320/S326 and inhibits CHIP-mediated HSF1 ubiquitination, thereby stabilizing and activating HSF1. Importantly, DBC1 loss suppresses growth and metastasis of mCRPC cells, and high DBC1 expression correlates with poor outcomes in patients with mCRPC. Our results highlight the critical role of DBC1 as a key HSF1 coregulator in mCRPC progression and provide insights into regulatory mechanisms of HSF1 stability and activity in advanced and metastatic cancers.
2025-09-02 | GSE276302 | GEO
Project description:Heat shock factor 1 (HSF1) is a key stress-protective transcription factor that is exploited by various cancers to promote cancer cell survival, therapy resistance, and metastasis. Metastatic castration-resistant prostate cancer (mCRPC) is the leading cause of cancer-related death in men worldwide, and mCRPC progression is associated with increased dependence on HSF1. However, mechanisms underlying HSF1 stabilization and persistent activation in metastatic malignancies remain unclear. Here we show that the HSF1-driven transcriptional program and its genome occupancy in mCRPC cells are distinct from those of CRPC cells. HSF1 is highly activated and required for the metastatic potential of mCRPC cells. Moreover, we report DBC1 as a critical regulator of HSF1 stability and activity in mCRPC cells. DBC1 is required for genome-wide chromatin occupancy and target gene expression of HSF1. Mechanistically, DBC1 enhances DYRK2/PKA-mediated HSF1 phosphorylation at S320/S326 and inhibits CHIP-mediated HSF1 ubiquitination, thereby stabilizing and activating HSF1. Importantly, DBC1 loss suppresses growth and metastasis of mCRPC cells, and high DBC1 expression correlates with poor outcomes in patients with mCRPC. Our results highlight the critical role of DBC1 as a key HSF1 coregulator in mCRPC progression and provide insights into regulatory mechanisms of HSF1 stability and activity in advanced and metastatic cancers.
2025-09-02 | GSE276301 | GEO
Project description:Anthracycline-based chemotherapy resistance represents a major challenge in diffuse large B-cell lymphoma (DLBCL). MiRNA and gene expression profiles (n = 47) were determined to uncover potential chemoresistance mechanisms and therapeutic approaches. An independent correlation between high expression of miRNA-363-3p and chemoresistance was observed and validated in a larger cohort (n = 106). MiRNA-363-3p was shown to reduce doxorubicin-induced apoptosis and tumor shrinkage in in vitro and in vivo experiments by ectopic expression and CRISPR/Cas9-mediated knockout in DLBCL cell lines. DNA methylation was found to participate in transcriptional regulation of miRNA-363-3p. Further investigation revealed that dual specificity phosphatase 10 (DUSP10) is a target of miRNA-363-3p and its suppression promotes the phosphorylation of c-Jun N-terminal kinase (JNK). The miRNA-363-3p/DUSP10/JNK axis was predominantly associated with negative regulation of homologous recombination (HR) and DNA repair pathways. Ectopic expression of miRNA-363-3p more effectively repaired doxorubicin-induced double-strand break (DSB) while enhancing non-homologous end joining repair and reducing HR repair. Targeting JNK and poly (ADP-ribose) polymerase 1 significantly inhibited doxorubicin-induced DSB repair, increased doxorubicin-induced cell apoptosis and tumor shrinkage, and improved the survival of tumor-bearing mice. In conclusion, the miRNA-363-3p/DUSP10/JNK axis is a novel chemoresistance mechanism in DLBCL that may be reversed by targeted therapy.
| S-EPMC9252898 | biostudies-literature
Project description:IRF4 contributes to chemoresistance in IGH-BCL2 positive diffuse large B-cell lymphomas by mediating BCL2 induced SOX9 expression
| PRJNA1165689 | ENA
Project description:RC-DLBCL (Diffuse Large-B Cell Lymphomas)
| PRJNA1311170 | ENA
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11
2002-06-27 | E-GEOD-60 | biostudies-arrayexpress