The role of tripartite motif-containing 28 in cancer progression and its therapeutic potentials

Yang, Yi‐Qing; Tan, Shiming; Han, Yang; Huang, Lisheng; Yang, Ruiqian; Hu, Zifan; Yi, Tao; Oyang, Linda; Lin, Jinguan; Qiu, Ping; Jiang, Xianjie; Xu, Xuemeng; Xia, Longzheng; Wu, Nayiyuan; Tang, Yue; Li, Xiaoling; Liao, Qianjin; Zhou, Yujuan

doi:10.3389/fonc.2023.1100134

Cited by 14 publications

(10 citation statements)

References 103 publications

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“…These novel findings differ from TRIM28’s published roles 42,98 that include context-specific oncogene 99–109 and tumor suppressor 110–115 functions, roles that were primarily determined from complete (homozygous) knockouts. In contrast to homozygous knockout models, the Trim28 +/D9 haplo-insufficient mouse exhibits near normal levels of TRIM28 throughout the body 44 .…”

Section: Discussioncontrasting

confidence: 80%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility ′states′ in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

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Section: Discussioncontrasting

confidence: 80%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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“…There have been studies constructing prognosis models based on copper death features, but they have not comprehensively considered clinical features, and the explanation of the genetic molecular landscape is not in‐depth enough [37]. There is no cross‐validation between drug screening and cell line sensitivity, and no sensitivity‐related experiments have been conducted to verify the screened drugs [38]. A column chart model combining risk scores and other clinical pathological features has been constructed based on copper death features and tumor microenvironment single cell profiles, but its application and screening of effective drugs based on clinical features and molecular landscapes of gastric cancer are not detailed enough [39].…”

Section: Discussionmentioning

confidence: 99%

Clinical features and molecular landscape of cuproptosis signature‐related molecular subtype in gastric cancer

Chong,

Ren,

Chen

et al. 2024

iMeta

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Recent studies have highlighted the biological significance of cuproptosis in disease occurrence and development. However, it remains unclear whether cuproptosis signaling also has potential impacts on tumor initiation and prognosis of gastric cancer (GC). In this study, 16 cuproptosis‐related genes (CRGs) transcriptional profiles were harnessed to perform the regularized latent variable model‐based clustering in GC. A cuproptosis signature risk scoring (CSRS) scheme, based on a weighted sum of principle components of the CRGs, was used to evaluate the prognosis and risk of individual tumors of GC. Four distinct cuproptosis signature‐based clusters, characterized by differential expression patterns of CRGs, were identified among 1136 GC samples across three independent databases. The four clusters were also associated with different clinical outcomes and tumor immune contexture. Based on the CSRS, GC patients can be divided into CSRS‐High and CSRS‐Low subtypes. We found that DBT, MTF1, and ATP7A were significantly elevated in the CSRS‐High subtype, while SLC31A1, GCSH, LIAS, DLAT, FDX1, DLD, and PDHA1 were increased in the CSRS‐Low subtype. Patients with CSRS‐Low score were characterized by prolonged survival time. Further analysis indicated that CSRS‐Low score also correlated with greater tumor mutation burden (TMB) and higher mutation rates of significantly mutated genes (SMG) in GC. In addition, the CSRS‐High subtype harbored more significantly amplified focal regions related to tumorigenesis (3q27.1, 12p12.1, 11q13.3, etc.) than the CSRS‐Low tumors. Drug sensitivity analyses revealed the potential compounds for the treatment of gastric cancer with CSRS‐High score, which were experimentally validated using GC cells. This study highlights that cuproptosis signature‐based subtyping is significantly associated with different clinical features and molecular landscape of GC. Quantitative evaluation of the CSRS of individual tumors will strengthen our understanding of the occurrence and development of cuproptosis and the treatment progress of GC.

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“…The tumor suppressive function exerted by TRIM28 is closely tied to its control over the expression of pro-tumorigenic chemokines [ 39 ]. Elevated levels of CXCL1 in tumors have been shown to play a fundamental role in tumor malignancy and metastasis across various cancer types.…”

Section: Discussionmentioning

confidence: 99%

E3 ligase TRIM28 promotes anti-PD-1 resistance in non-small cell lung cancer by enhancing the recruitment of myeloid-derived suppressor cells

Liang,

Sun,

Chen

et al. 2023

J Exp Clin Cancer Res

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Background Alterations in several tripartite motif-containing (TRIM) family proteins have been implicated in the pathogenesis of lung cancer. TRIM28, a member of the TRIM E3 ligase family, has been associated with tumorigenesis, cell proliferation, and inflammation. However, little is known about TRIM28 expression and its role in the immune microenvironment of non-small cell lung cancer (NSCLC). Methods We assessed the clinical significance of TRIM28 in tissue microarrays and TCGA cohorts. We investigated the function of TRIM28 in syngeneic mouse tumor models, the KrasLSL−G12D/+; Tp53fl/fl (KP) mouse model, and humanized mice. Immune cell composition was analyzed using flow cytometry and immunohistochemistry. Results Our findings revealed a positive correlation between TRIM28 expression and the infiltration of suppressive myeloid-derived suppressor cells (MDSCs) in NSCLC. Moreover, silencing TRIM28 enhanced the efficacy of anti-PD-1 immunotherapy by reshaping the inflamed tumor microenvironment. Mechanistically, we demonstrated that TRIM28 could physically interact with receptor-interacting protein kinase 1 (RIPK1) and promote K63-linked ubiquitination of RIPK1, which is crucial for sustaining activation of the NF-κB pathway. Mutagenesis of the E3 ligase domain corroborated the essential role of E3 ligase activity in TRIM28-mediated NF-κB activation. Further experiments revealed that TRIM28 could upregulate the expression of CXCL1 by activating NF-κB signaling. CXCL1 could bind to CXCR2 on MDSCs and promote their migration to the tumor microenvironment. TRIM28 knockdown increased responsiveness to anti-PD-1 therapy in immunocompetent mice, characterized by increased CD8+T tumor-infiltrating lymphocytes and decreased MDSCs. Conclusion The present study identified TRIM28 as a promoter of chemokine-driven recruitment of MDSCs through RIPK1-mediated NF-κB activation, leading to the suppression of infiltrating activated CD8+T cells and the development of anti-PD-1 resistance. Understanding the regulation of MDSC recruitment and function by TRIM28 provides crucial insights into the association between TRIM28 signaling and the development of an immunosuppressive tumor microenvironment. These insights may inform the development of combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in NSCLC.

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The role of tripartite motif-containing 28 in cancer progression and its therapeutic potentials

Cited by 14 publications

References 103 publications

Developmental priming of cancer susceptibility

Developmental priming of cancer susceptibility

Clinical features and molecular landscape of cuproptosis signature‐related molecular subtype in gastric cancer

E3 ligase TRIM28 promotes anti-PD-1 resistance in non-small cell lung cancer by enhancing the recruitment of myeloid-derived suppressor cells

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