2. Academic Validation
  3. The m6A reader IGF2BP3 preserves NOTCH3 mRNA stability to sustain Notch3 signaling and promote tumor metastasis in nasopharyngeal carcinoma

The m6A reader IGF2BP3 preserves NOTCH3 mRNA stability to sustain Notch3 signaling and promote tumor metastasis in nasopharyngeal carcinoma

  • Oncogene. 2023 Oct 18. doi: 10.1038/s41388-023-02865-6.
Boyu Chen # 1 2,  Runda Huang # 1 3,  Tianliang Xia # 1 2,  Chunyang Wang 4,  Xiao Xiao 1 5,  Shunzhen Lu 1 5,  Xiangfu Chen 1 2,  Ying Ouyang 1 2,  Xiaowu Deng 1 3,  Jingjing Miao 6 7,  Chong Zhao 8 9,  Lin Wang 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 2 Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • 3 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • 4 Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510060, P. R. China.
  • 5 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. miaojj@sysucc.org.cn.
  • 7 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. miaojj@sysucc.org.cn.
  • 8 State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. gzzhaochong@hotmail.com.
  • 9 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. gzzhaochong@hotmail.com.
  • 10 State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. wangl1@sysucc.org.cn.
  • 11 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. wangl1@sysucc.org.cn.
  • # Contributed equally.
PMID: 37853162 DOI: 10.1038/s41388-023-02865-6
Abstract

Metastasis remains the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC), in which sustained activation of the Notch signaling plays a critical role. N6-Methyladenosine (m6A)-mediated post-transcriptional regulation is involved in fine-tuning the Notch signaling output; however, the post-transcriptional mechanisms underlying NPC metastasis remain poorly understood. In the present study, we report that insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) serves as a key m6A reader in NPC. IGF2BP3 expression was significantly upregulated in metastatic NPC and correlated with poor prognosis in patients with NPC. IGF2BP3 overexpression promoted, while IGF2BP3 downregulation inhibited tumor metastasis and the stemness phenotype of NPC cells in vitro and in vivo. Mechanistically, IGF2BP3 maintains NOTCH3 mRNA stability via suppression of CCR4-NOT complex-mediated deadenylation in an m6A-dependent manner, which sustains Notch3 signaling activation and increases the transcription of stemness-associated downstream genes, eventually promoting tumor metastasis. Our findings highlight the pro-metastatic function of the IGF2BP3/Notch3 axis and revealed the precise role of IGF2BP3 in post-transcriptional regulation of NOTCH3, suggesting IGF2BP3 as a novel prognostic biomarker and potential therapeutic target in NPC metastasis.

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