EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers

Xiang-jin Zheng1,2, Wan Li1,2, Jie Yi3, Jin-yi Liu1,2, Li-wen Ren1,2, Xiao-ming Zhu4, Shi-wei Liu5, Jin-hua Wang1,2, Guan-hua Du1,2
1 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China
2 Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
3 Department of Clinical Laboratory, Peking Union Medical College Hospital, Beijing 100032, China
4 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China
5 Department of Endocrinology, Shanxi DAYI Hospital, Shanxi Medical University, Taiyuan 030002, China
Correspondence to: Jin-hua Wang:, Guan-hua Du:,
DOI: 10.1038/s41401-020-00543-x
Received: 22 March 2020
Accepted: 16 September 2020
Advance online: 14 October 2020


Triple-negative breast cancer (TNBC) is characterized by low expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), which is the most aggressive subtype with poor outcome among breast cancers. The underlying mechanisms of TNBC remain unclear and there is a lack of biomarkers. In this study we conducted an in silico assay and found that FOXC1 was highly expressed in ER−/PR−/HER2− breast cancers, which was confirmed by qRT-PCR, immunohistochemistry, and Western blot analysis. FOXC1 was more highly expressed in TNBCs than the other breast cancers. Kaplan–Meier plotter revealed that expression of FOXC1 was associated with overall survival (OS) of patients with breast cancers. Expression of FOXC1 was reversely associated with level of H3K27me3, which was methylated by EZH2. In MCF-7 and T47D cells, inhibition of EZH2 by DZNeP or GSK343 concentration- and time-dependently increased expression of FOXC1. Finally, we demonstrated that the expression of FOXC1 was associated with resistance of doxorubicin treatment of breast cancer cells. In conclusion, these results suggest that FOXC1 may be a potential biomarker or drug target for TNBCs, and that downregulation of FOXC1 could have therapeutic value in treatment of TNBCs.
Keywords: TNBC; FOXC1; EZH2; H3K27me3; drug resistance

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