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Updated: Dec 8, 2025

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic

Ga-Young Jeong1, Mi Kyung Park2, Hee-Joo Choi1,3

  • 1Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.

Cancer Research
|September 24, 2020
PubMed

Insights

Histone methyltransferase NSD3 drives breast cancer initiation and metastasis by regulating H3K36 methylation and NOTCH signaling. Targeting NSD3 offers a new therapeutic strategy for aggressive breast cancer.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Histone methyltransferase NSD3 is frequently dysregulated in human cancers.
  • The precise epigenetic role of NSD3 in cancer development, particularly breast cancer, is not fully understood.

Purpose of the Study:

  • To elucidate the epigenetic role of NSD3 in breast tumor initiation and metastasis.
  • To investigate the molecular mechanisms by which NSD3 influences breast cancer progression.
  • To evaluate NSD3 as a potential therapeutic target in breast cancer.

Main Methods:

  • Analysis of NSD3 expression in patient data and correlation with clinical outcomes.
  • In vivo studies using mouse models to assess NSD3's role in mammary epithelial cell transformation and metastasis.
  • Mechanistic studies involving gene expression analysis, protein-protein interactions (NSD3, EZH2, RNA polymerase II), and NOTCH signaling pathway investigation.
  • Assessment of therapeutic efficacy of NOTCH inhibition in NSD3-overexpressing tumors.

Main Results:

  • Elevated NSD3 expression in breast cancer patients correlates with recurrence, distant metastasis, and poor survival.
  • NSD3 promotes malignant transformation, expands cancer-initiating cells, and drives epithelial-mesenchymal transition (EMT) in breast cancer.
  • The full-length NSD3 isoform cooperates with EZH2 and RNA polymerase II to regulate H3K36 methylation, impacting NOTCH signaling, NICD accumulation, and E-cadherin repression.
  • Mice with NSD3-overexpressing tumors showed sensitivity to NOTCH inhibition.

Conclusions:

  • NSD3 plays a critical epigenetic role in breast cancer stemness, EMT, and metastasis through modulation of NOTCH signaling.
  • The NSD3-NOTCH signaling axis represents a promising therapeutic target for aggressive and metastatic breast cancer.

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