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TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of β-catenin

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Abstract

Purpose

TRAF4 plays an important role in the development and progression of breast cancer, but its impact on chemotherapy resistance is as yet, however, poorly understood.

Methods

Western blotting, immunoprecipitation, and immunofluorescence staining were used to identify and verify that TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated β-catenin degradation. Cell proliferation analysis and Flow cytometry analysis were utilized to detect TRAF4′s function on the growth-inhibitory effect of etoposide. Immunohistochemistry was used to detect the expression of TRAF4, SIAH1, and β-catenin. Statistical analysis was used to analyze the relationships between them with clinical parameters and curative effect of chemotherapy pathologically.

Results

Our results suggested that TRAF4 prevents SIAH1-mediated β-catenin degradation. TRAF4 was a novel substrate of SIAH1 and the TRAF domain of TRAF4 was critical for binding to SIAH1. TRAF4 reduced the growth-inhibitory effect of etoposide via reducing the number of S-phase cells and suppressing cell apoptosis. Concordantly, we found that breast cancer patients with a low-TRAF4 expression benefited most from chemotherapy, who had higher tumor volume reduction rate and better pathological response, while, the high-TRAF4 expression group had lower tumor volume reduction rate and poor pathological response.

Conclusions

TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated β-catenin degradation, which explains the protective effect of TRAF4 on β-catenin during cell stress and links TRAF4 to chemotherapy resistance in tumors. These findings implicated a novel pathway for the oncogenic function of TRAF4.

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Abbreviations

TRAFs:

Tumor necrosis factor receptor associated factors

SIAH1:

Seven in absentia homolog

NF-kB:

Nuclear factor kappaB

JNK:

C-Jun N-terminal kinase

TNFR:

Tumor necrosis factor receptor

GIRT:

Glucocorticoid-induced TNFR

p70s6k:

70 KDa ribosomal protein S6 kinase

Tcf/LEF:

T cell factor/lymphoid enhancer factor

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Acknowledgements

We thank Dr. Bert W. O’Malley (Baylor College of Medicine) for kindly providing the Flag-ΔZn TRAF4 expression vector. We thank Dr Min Song (China Medical University) for kindly providing the wild-type SIAH1 and ΔR-SIAH1 plasmids.

Funding

This study was funded by National Natural Science Foundation of China, Grant Number 81803011.

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Authors and Affiliations

  1. Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Huayan Ren, Pengyuan Zhao, Xueyan Zhao, Na Wei, Huifen Huang, Zhongqin Meng, Junna Kou, Yuqiong Liu, Hongyan Zhang, Jianping Yang, Wencai Li & Huixiang Li

  2. College of Basic Medical Sciences, Zhengzhou University, Jianshe Road 1, Erqi Ward, Zhengzhou, 450052, P.R. China

    Huayan Ren, Pengyuan Zhao, Xueyan Zhao, Na Wei, Huifen Huang, Zhongqin Meng, Junna Kou, Yuqiong Liu, Hongyan Zhang, Jianping Yang, Wencai Li & Huixiang Li

  3. Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, China

    Xiaoyi Mi & Mingfang Sun

Authors
  1. Huayan Ren
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  2. Xiaoyi Mi
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  14. Huixiang Li
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Contributions

All authors meet the authorship requirements. Huayan Ren participated in the design of the study, drafted the manuscript and performed the experiments. Xiaoyi Mi, Pengyuan Zhao, Xueyan Zhao, Na Wei, Huifen Huang, Zhongqin Meng, Junna Kou, Xueliang Fan analyzed the data and performed the statistical analysis. Hongyan Zhang, Jianping Yang, and Wencai Li prepared the figures. Huixiang Li conceived and designed the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Huixiang Li.

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Ren, H., Mi, X., Zhao, P. et al. TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of β-catenin. Breast Cancer Res Treat 183, 275–289 (2020). https://doi.org/10.1007/s10549-020-05789-x

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