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

Jun Jian Wang, June X Zou, Hong Wang, Zhi Jian Duan, Hai Bin Wang, Peng Chen, Pei Qing Liu, Jian Zhen Xu, Hongwu Chen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalActa Pharmacologica Sinica
DOIs
StateAccepted/In press - Jan 1 2019

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Triple Negative Breast Neoplasms
Survival
Histone-Lysine N-Methyltransferase
Disintegrins
histone methyltransferase
Metalloproteases
Cytoplasmic and Nuclear Receptors
Epigenomics
Neoplasms
Cell Survival
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Therapeutics
Breast Neoplasms

Keywords

  • Cell invasion
  • Cell survival
  • EGFR
  • Histone methyltransferase
  • NSD2
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Histone methyltransferase NSD2 mediates the survival and invasion of triple-negative breast cancer cells via stimulating ADAM9-EGFR-AKT signaling. / Wang, Jun Jian; Zou, June X; Wang, Hong; Duan, Zhi Jian; Wang, Hai Bin; Chen, Peng; Liu, Pei Qing; Xu, Jian Zhen; Chen, Hongwu.

In: Acta Pharmacologica Sinica, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Duan, Zhi Jian

AU - Wang, Hai Bin

AU - Chen, Peng

AU - Liu, Pei Qing

AU - Xu, Jian Zhen

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