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SREBP1, targeted by miR-18a-5p, modulates epithelial-mesenchymal transition in breast cancer via forming a co-repressor complex with Snail and HDAC1/2

Cell Death & Differentiation (2018) | Download Citation

Abstract

The progression of localized breast cancer to distant metastasis results in a poor prognosis and a high mortality rate. In this study, the contributions of miRNAs to tumor progression and the regulatory mechanisms leading to their expression alterations were investigated. Using highly lung-metastatic sub-lines from parental breast cancer cells, miRNA expression profiling revealed that the miR-17-92 cluster is significantly downregulated and the miR-18a-5p is the most evidently decreased. Ectopic expression and inhibition of miR-18a-5p demonstrated its capacity in suppressing migration and invasion of breast cancer cells. Further research identified sterol regulatory element binding transcription protein 1 (SREBP1), the master transcription factor that controls lipid metabolism, as a candidate target of miR-18a-5p. SREBP1 is overexpressed and strongly associated with worse clinical outcomes in breast cancer. Functionally SREBP1 promotes growth and metastasis of breast cancer both in vitro and in vivo. To unravel the underlying mechanism of SREBP1-mediated metastasis, mRNA profiling and subsequent gene set enrichment analyses (GSEA) were performed and SREBP1 was demonstrated to be significantly associated with epithelial-mesenchymal transition (EMT). Furthermore, SREBP1-mediated repression of E-cadherin was found to be deacetylation dependent and was augmented by recruiting Snail/HDAC1/2 repressor complex. In the light of these data, we propose that reduced expression of miR-18a-5p and concomitant overexpression of SREBP1 lead to induction of EMT states that in turn, promote breast cancer progression and metastasis. Taken together, our study reveals the crucial role of miR-18a-5p and SREBP1 in the EMT and metastasis, thus providing promising drug targets for tailored therapy in the advanced breast cancer setting.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81502285, No.81672613, No.81272903), Key Research and Development Program of Shandong Province (No. 2016GSF201119), Shandong Science and Technology Development Plan (2016CYJS01A02), Shandong Provincial Natural Science Foundation of China (No. ZR2017BH050), Special Support Plan for National High Level Talents (“Ten Thousand Talents Program”) to QY and China Postdoctoral Science Foundation to NZ (No. 2018M630787).

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Affiliations

  1. Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, Shandong, China

    • Ning Zhang
    • , Hanwen Zhang
    • , Ying Liu
    • , Jiashu Zhang
    • , Xiaolong Wang
    •  & Qifeng Yang
  2. Department of Pathology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China

    • Peng Su
  3. Shandong Cancer Hospital affiliated to Shandong University, Ji’nan, Shandong, China

    • Mingjuan Sun
  4. Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji’nan, Shandong, China

    • Bing Chen
    • , Wenjing Zhao
    • , Lijuan Wang
    •  & Qifeng Yang
  5. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China

    • Huiyun Wang
  6. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA

    • Meena S. Moran
  7. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    • Bruce G. Haffty

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The authors declare that they have no conflict of interest.

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Correspondence to Qifeng Yang.

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https://doi.org/10.1038/s41418-018-0158-8