Histone methyltransferase NSD2 mediates the survival and invasion of triple-negative breast cancer cells via stimulating ADAM9-EGFR-AKT signaling

Jun-Jian Wang1,2, June X. Zou2, Hong Wang1, Zhi-Jian Duan2, Hai-Bin Wang3, Peng Chen3, Pei-Qing Liu1, Jian-Zhen Xu4, Hong-Wu Chen2,5
1 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
2 Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA
3 First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
4 Computational Systems Biology Lab, Shantou University Medical College, Shantou 515041, China
5 Comprehensive Cancer Center, University of California, Davis, School of Medicine, Sacramento, CA, USA
Correspondence to: Jian-Zhen Xu:, Hong-Wu Chen:,
DOI: 10.1038/s41401-018-0199-z
Received: 7 June 2018
Accepted: 23 November 2018
Advance online: 22 January 2019


Triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis due to the lack of an effective targeted therapy. Histone lysine methyltransferases (KMTs) have emerged as attractive drug targets for cancer therapy. However, the function of the majority of KMTs in TNBC has remained largely unknown. In the current study, we found that KMT nuclear receptor binding SET domain protein 2 (NSD2) is overexpressed in TNBC tumors and that its overexpression is associated with poor survival of TNBC patients. NSD2 regulates TNBC cell survival and invasion and is required for tumorigenesis and tumor growth. Mechanistically, NSD2 directly controls the expression of EGFR and ADAM9, a member of the ADAM (a disintegrin and metalloproteinase) family that mediates the release of growth factors, such as HB-EGF. Through its methylase activity, NSD2 overexpression stimulates EGFR-AKT signaling and promotes TNBC cell resistance to the EGFR inhibitor gefitinib. Together, our results identify NSD2 as a major epigenetic regulator in TNBC and provide a rationale for targeting NSD2 alone or in combination with EGFR inhibitors as a targeted therapy for TNBC.
Keywords: NSD2; Cell survival; Cell invasion; Histone methyltransferase; Triple-negative breast cancer; EGFR

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