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Tripartite-motif 3 represses ovarian cancer progression by downregulating lactate dehydrogenase A and inhibiting AKT signaling

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Abstract

The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells.

Graphical abstract

Our study mainly investigated the role and mechanism of the E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) in the progression of ovarian cancer. As a tumor suppressor, TRIM3 interact directly with LDHA and promotes the ubiquitination and degradation of LDHA, which plays a crucial role in the conversion of pyruvate and NADH to L-lactate and NAD in the final step of anaerobic glycolysis, thereby inhibiting glycolysis in ovarian cancer cells. Furthermore, overexpression of TRIM3 also reduces the phosphorylation of AKT independently of the interaction between TRIM3 and LDHA. In summary, our findings demonstrated that TRIM3 could inhibit ovarian cancer progression by downregulating LDHA and suppressing the AKT signaling pathway.

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Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

TRIM3:

The E3 ubiquitin ligase Tripartite-motif 3

FIGO:

International federation of gynecology and obstetrics

GEPIA:

Gene expression profiling interactive analysis

TCGA:

The cancer genome atlas

GTEx:

Genome-tissue expression

ECAR:

Extracellular acidification rate

PFK1:

Phosphofructokinase 1

PFKP:

Phosphofructokinase 1 platelet type

PFKM:

Phosphofructokinase 1 muscle type

PFKL:

Phosphofructokinase 1 liver type

GLUT1:

Glucose transporter protein

LDHA:

Lactate dehydrogenase A

GO:

Gene ontology

KEGG:

Kyoto encyclopedia of genes and genomes

UPS:

Ubiquitin-proteasome system

TBST:

Tris-buffered saline containing 0.1% Tween-20

CHX:

Cycloheximide

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Funding

This study was financially supported by Jiangsu provincial key research and development program (Grant No: BE2020753, BE2019621), Jiangsu Provincial Medical Talent (Xuemei Jia), Nanjing Medical Science and Technique Development Foundation (Grant No: ZDX16015). Jiangsu Province Capability Improvement Project through Science, Technology and Education Jiangsu Provincial Medical Key Discipline (ZDXK202211).

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  1. Yu Cong and Xin Cui have contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China

    Yu Cong, Xin Cui, Yaqian Shi, Xinxing Pan, Ke Huang, Zhe Geng, Lili Ge, Juan Xu & Xuemei Jia

  2. Nanjing Maternal and Child Health Care Institute, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital), Nanjing, 210004, Jiangsu, China

    Pengfei Xu

  3. Department of Epidemiology and Microbiology, Huadong Medical Institute of Biotechniques, Nanjing, 210002, Jiangsu, China

    Jin Zhu

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  1. Yu Cong
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Contributions

All authors contributed to the study conception and design. XJ and JX: Conceptualization, Supervision and Funding acquisition; YC and XC: Investigation, Methodology, Validation, writing-original draft; YS and XP: Methodology, Visualization and Formal Analysis; KH and ZG: Methodology, Resources; PX, LG and JZ: Resources and Data curation. All authors read and approved the final manuscript.

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Correspondence to Juan Xu or Xuemei Jia.

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The experimental protocol and method were approved by the Ethics Committee of Women′s Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital) and followed the Declaration of Helsinki (Approved number: 2022KY-176, approved on 2-10-2023). Informed consents were obtained from all participates. The in vivo experiments were approved by the ethics committee of Nanjing Medical University (Approved number: IACUC-2208015, approved on 8-18-2022).

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Cong, Y., Cui, X., Shi, Y. et al. Tripartite-motif 3 represses ovarian cancer progression by downregulating lactate dehydrogenase A and inhibiting AKT signaling. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-023-04920-y

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