Archives of Pharmacal Research

, Volume 42, Issue 6, pp 519–530 | Cite as

The YB-1/EZH2/amphiregulin signaling axis mediates LPA-induced breast cancer cell invasion

  • Kyung Hwa Cho
  • Bo Young Jeong
  • Chang Gyo ParkEmail author
  • Hoi Young LeeEmail author
Research Article


Lysophosphatidic acid (LPA) has been known to induce epithelial-mesenchymal transition (EMT) to stimulate cancer cell invasion, and resveratrol (3,5,4′-trans-trihydroxystilbene; REV) suppresses the invasion and metastasis of various cancers. The current study aimed to identify the underlying mechanism by which LPA aggravates breast cancer cell invasion and the reversal of this phenomenon. Immunoblotting and quantitative RT-PCR analysis revealed that LPA induces amphiregulin (AREG) expression. Silencing of Y-box binding protein 1 (YB-1) or enhancer of zeste homolog 2 (EZH2) expression efficiently inhibited LPA-induced AREG expression. In addition, transfection of the cells with YB-1 siRNA abrogated LPA-induced EZH2 and AREG expression, leading to attenuation of breast cancer cell invasion. Furthermore, we observed that both REV and 5-fluorouracil (5-Fu) significantly reduce LPA-induced YB-1 phosphorylation and subsequent breast cancer invasion. Importantly, combined treatment of REV with 5-Fu showed more significant inhibition of LPA-induced breast cancer invasion compared to single treatment. Therefore, our data demonstrate that the YB-1/EZH2 signaling axis mediates LPA-induced AREG expression and breast cancer cell invasion and its inhibition by REV and 5-Fu, providing potential therapeutic targets and inhibition of breast cancer.


Lysophosphatidic acid Resveratrol Breast cancer Invasion Amphiregulin 



This study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [NRF-2017R1E1A1A01074091, 2016R1D1A1B04930418, 2017R1A2B4007361].

Compliance with ethical standards

Conflict of interest

The authors declare no conflict interest.


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Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, College of MedicineKonyang UniversityDaejeonRepublic of Korea

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