Tumor necrosis factor receptor-associated factor 4 (TRAF4), an E3 ubiquitin ligase, is frequently overexpressed in tumors. Although its cytoplasmic role in tumor progression is well-documented, the precise mechanisms underlying its nuclear localization and functional contributions in tumor cells remain elusive. This study demonstrated a positive correlation between the expression of nuclear TRAF4 and both tumor grades and stemness signatures in human cancer tissues. Notably, reduced nuclear TRAF4 led to decreased stemness properties and metastatic dormancy of tumor cells. Conversely, restoring nuclear TRAF4 in TRAF4-knockout (TRAF4-KO) cells augmented these cellular capabilities. Within the nucleus, the TRAF domain of TRAF4 interacted with c-Jun, thereby stimulating its transcriptional activity. This interaction subsequently led to an enhancement of the promoter activity of interleukin-8 (IL-8), which is identified as a mediator of nuclear TRAF4-induced tumor dormancy. Additionally, activation of AKT signaling by nerve growth factor facilitated TRAF4 phosphorylation at Ser242, enhancing its interaction with 14-3-3θ and promoting its nuclear translocation. Importantly, pharmacological modulation of TRAF4 nuclear translocation is found to suppress tumor tumorigenicity and metastasis in tumor models. This study highlights the critical role of nuclear TRAF4 in regulating tumor stemness and dormancy, positioning it as a potential therapeutic target for metastatic and refractory cancers.
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http://dx.doi.org/10.1002/advs.202414437 | DOI Listing |
Adv Sci (Weinh)
December 2024
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
Tumor necrosis factor receptor-associated factor 4 (TRAF4), an E3 ubiquitin ligase, is frequently overexpressed in tumors. Although its cytoplasmic role in tumor progression is well-documented, the precise mechanisms underlying its nuclear localization and functional contributions in tumor cells remain elusive. This study demonstrated a positive correlation between the expression of nuclear TRAF4 and both tumor grades and stemness signatures in human cancer tissues.
View Article and Find Full Text PDFFront Oncol
May 2024
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Background: Triple-negative breast cancer (TNBC) cells are a highly formidable cancer to treat. Nonetheless, by continued investigation into the molecular biology underlying the complex regulation of TNBC cell activity, vulnerabilities can be exposed as potential therapeutic targets at the molecular level. We previously revealed that lysyl oxidase-like 4 (LOXL4) promotes the invasiveness of TNBC cells via cell surface annexin A2 as a novel binding substrate of LOXL4, which promotes the abundant localization of integrin-β1 at the cancer plasma membrane.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
May 2023
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear.
View Article and Find Full Text PDFMicrobiol Spectr
February 2023
State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
The Aedes aegypti mosquito transmits devastating flaviviruses, such as Zika, dengue, and yellow fever viruses. For more effective control of the vector, the pathogenicity of Beauveria bassiana, a fungus commonly used for biological control of pest insects, may be enhanced based on in-depth knowledge of molecular interactions between the pathogen and its host. Here, we identified a mechanism employed by B.
View Article and Find Full Text PDFLife (Basel)
January 2022
Graduate Collaborative Training Base of Academy of Military Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.
Accurate dose assessment within 1 day or even 12 h after exposure through current methods of dose estimation remains a challenge, in response to a large number of casualties caused by nuclear or radiation accidents. P53 signaling pathway plays an important role in DNA damage repair and cell apoptosis induced by ionizing radiation. The changes of radiation-induced P53 related genes in the early stage of ionizing radiation should compensate for the deficiency of lymphocyte decline and γ-H2AX analysis as novel biomarkers of radiation damage.
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