O-GlcNAcylation of NSD2 promotes lung metastasis of triple-negative breast cancer through extracellular matrix remodeling

  • Biochem Biophys Res Commun. 2026 Aug 20:827:154043. doi: 10.1016/j.bbrc.2026.154043.
Sicheng Fu  1 ,  Chunju Yang  1 ,  Zhiping Liang  2 ,  Lin Zhong  3 ,  Shufeng Ji  2 ,  Yuanxiang Wang  1 ,  Junjian Wang  4 ,  Zhanfang Kang  5 ,  Junguo Bu  6 ,  Hong Wang  7
Affiliations
  • 1. State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
  • 2. Department of General Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510006, China.
  • 3. Department of Breast Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
  • 4. State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China; National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
  • 5. Guangdong Engineering Technology Research Center of Urinary Continence and Reproductive Medicine, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China. Electronic address: [email protected].
  • 6. Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong Province, 510280, China. Electronic address: [email protected].
  • 7. State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China. Electronic address: [email protected].
PMID: 42217410 DOI: 10.1016/j.bbrc.2026.154043
Abstract

Metastasis is the leading cause of treatment failure and poor prognosis in triple-negative breast Cancer (TNBC), underscoring the urgent need for effective therapeutic strategies. In this study, we show that O-GlcNAcylation catalyzed by O-GlcNAc transferase (OGT) increases NSD2 stability and thereby promotes TNBC metastasis. Mechanistically, OGT directly interacts with NSD2 and facilitates its O-GlcNAcylation, which impedes ubiquitin-mediated degradation and enhances NSD2 protein stability. OGT knockdown reduces NSD2 protein levels, downregulates extracellular matrix (ECM)-related signaling pathways, decreases Collagen production and cell-matrix adhesion, and ultimately inhibits TNBC cell invasion and tumor metastasis. Importantly, disruption of the OGT-NSD2 axis markedly suppresses metastasis in TNBC xenograft models. Together, these findings reveal a novel mechanism by which OGT drives tumor metastasis through modulation of NSD2 O-GlcNAcylation, and identify the OGT-NSD2 axis as a potential therapeutic target for advanced TNBC.

Keywords
Extracellular matrix (ECM); Histone methyltransferase NSD2; Metastasis; O-GlcNAcylation; Triple-negative breast cancer (TNBC).
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