2. Academic Validation
  3. NSUN2-mediated m5C modification of KDM6B mRNA enhances osteoclast differentiation and promotes breast cancer bone metastasis

NSUN2-mediated m5C modification of KDM6B mRNA enhances osteoclast differentiation and promotes breast cancer bone metastasis

  • Cancer Lett. 2025 Jul 19:631:217939. doi: 10.1016/j.canlet.2025.217939.
Ming Zhang 1,  Cheng Tang 2,  Shang Li 3,  Xinluan Jiang 3,  Bilan Li 3,  Yan Chen 3,  Que Zheng 3,  Yuting Tang 3,  Xiaoshu Zhu 3,  Lei Huang 4,  Hongyan Yuan 5,  Jue Wang 6,  Yongmei Yin 7,  Yucui Jin 8,  Changyan Ma 9
Affiliations

Affiliations

  • 1 Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China; Department of Reproductive Genetic Center, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, China.
  • 2 Department of Orthopaedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China.
  • 3 Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China.
  • 4 Department of Radiotherapy, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
  • 5 Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20007, USA.
  • 6 Division of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. Electronic address: wangjue200011@njmu.edu.cn.
  • 7 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. Electronic address: ymyin@njmu.edu.cn.
  • 8 Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China. Electronic address: jyc@njmu.edu.cn.
  • 9 Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China. Electronic address: cyma@njmu.edu.cn.
PMID: 40692065 DOI: 10.1016/j.canlet.2025.217939
Abstract

Bone metastasis frequently occurs in advanced breast Cancer (BCa) and is associated with poor prognosis. The pathogenesis of bone metastasis is driven by cross-communications within the tumor-bone microenvironment. In this study, we demonstrated that NSUN2, a 5-methylcytosine (m5C) methyltransferase, is significantly overexpressed in bone metastatic lesions of BCa compared to adjacent non-metastatic bone tissues. Overexpression of NSUN2 promoted osteoclast differentiation and osteolytic bone metastasis, whereas knockdown of NSUN2 had the opposite effects. Mechanistically, NSUN2 facilitates the degradation of lysine demethylase 6B (KDM6B) mRNA through m5C modification in a peptidylprolyl isomerase A (PPIA)-dependent manner. Reduced KDM6B leads to hypermethylation of NUMB, disrupting its interaction with the Notch1 intracellular domain (NICD1). Consequently, the Notch signaling pathway is activated, leading to upregulated RANKL expression and accelerated osteoclast differentiation, which contributes to osteolytic bone metastasis. Strikingly, activating KDM6B expression with paricalcitol or inhibiting the Notch pathway with DAPT effectively counteracted NSUN2-induced osteolytic bone metastasis in vivo. Collectively, our findings underscore the pivotal role of the NSUN2-KDM6B-Notch axis in promoting osteoclast differentiation and bone metastasis in BCa, providing potential therapeutic targets for BCa patients with bone metastasis.

Keywords

Bone metastasis; KDM6B; NSUN2; Notch pathway; m(5)C modification.

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