IRF4 as an Oncogenic Master Transcription Factor

Wong, Regina Wan Ju; Ong, Jolynn Zu Lin; Theardy, Madelaine Skolastika; Sanda, Takaomi

doi:10.3390/cancers14174314

Cited by 18 publications

(12 citation statements)

References 111 publications

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“…In addition, we also observed that 14g or 14h significantly down-regulated other proteins (Figure 8A,B and Figure S3), such as TP53RK, 69 STAT1, 70 STAT2, 71 IRF4, 72,73 CDK5, 74 and KRAS. 75,76 Studies have shown that these proteins are closely related to the occurrence and development of hematological malignancies.…”

mentioning

confidence: 57%

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity

Hu,

Xu,

et al. 2024

J. Med. Chem.

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The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC 50 values and effectively degraded CBP and p300 proteins in a concentration-and time-dependent manner. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN-and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.

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confidence: 57%

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity

Hu,

Xu,

et al. 2024

J. Med. Chem.

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“…Unlike other IRFs, IRF4 is a unique family member that is not regulated by interferons (IFNs) ( 22 ), instead, is mainly induced upon T-cell receptor (TCR) signaling, Toll-like receptors (TLRs; such as TLR4 and TLR9) and tumor necrosis factor receptors. The expression of IRF4 is restricted to immune cells, including T and B cells, macrophages and DCs ( 19 , 22 ). In naïve T cells, IRF4 is expressed at low levels ( 23 ); however, following TCR signaling it is immediately induced and mediates critical immune responses by interacting with upstream signaling pathways, such as the TCR signaling, and its diverse binding partners ( 26 ).…”

Section: Structure and Function Of Irf4mentioning

confidence: 99%

“…Interferon regulatory factor 4 (IRF4) is a member of the interferon regulatory factor (IRF) family, and its unique characteristics and the importance in multiple biological processes have been highlighted by oncology and immunology. It first serves as an oncogene or a tumor suppressor in multiple types of lymphoid neoplasms ( 19 – 21 ). In addition, intriguingly, accumulating studies have demonstrated that IRF4 is a central determinant of differentiation, activation and effector function for various immune cells ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

Liang²,

Li³

et al. 2023

Front. Immunol.

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The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

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the oncogenic transcriptional program in malignant lymphoid cells 15 . However, research on the role of IRF4 in OSCC is still lacking 16 .In this study, we conducted a comprehensive bioinformatics analysis including functional enrichment analysis, CNV and immune infiltration analysis through Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to identify key genes and explore the underlying molecular mechanisms involved in OSF into OSCC.

…”

mentioning

confidence: 99%

“…the oncogenic transcriptional program in malignant lymphoid cells 15 . However, research on the role of IRF4 in OSCC is still lacking 16 .…”

mentioning

confidence: 99%

IRF4 as a novel target involved in malignant transformation of oral submucous fibrosis into oral squamous cell carcinoma

Jiang

You

et al. 2023

Sci Rep

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Oral squamous cell carcinoma (OSCC) in the context of oral submucous fibrosis (OSF) has a high incidence owing to undefined pathogenesis. Identifying key genes and exploring the underlying molecular mechanisms involved in the conversion of OSF into OSCC are in urgent need. Differentially expressed genes (DEGs) between OSCC and OSF were dug from GEO databases and a total of 170 DEGs were acquired. Functional association of DEGs were analyzed by GO and KEGG. Protein–protein interactions (PPIs) analysis was carried out and candidate biomarkers were identified by Gene co-expression analysis and Cox analyses. Hub genes were confirmed by qRT-PCR in tissues and cell lines, of which we found that IRF4 mRNA was successively up-regulated from Normal to OSF and then to OSCC and associated with immune infiltrating levels. In addition, Immunohistochemical (IHC) and Immunofluorescence (IF) assays were conducted to validate the consistent upregulation of IRF4 and the oncogene role of IRF4 in OSF and OSCC at translation level. IRF4 may be indicative biomarker in transformation of OSF into OSCC. High IRF4 expression contribute to increased immune infiltration of OSCC and may provide a novel diagnostic marker for OSCC patients translated from OSF.

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IRF4 as an Oncogenic Master Transcription Factor

Cited by 18 publications

References 111 publications

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

IRF4 as a novel target involved in malignant transformation of oral submucous fibrosis into oral squamous cell carcinoma

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