2. Academic Validation
  3. NONO promotes gallbladder cancer cell proliferation by enhancing oncogenic RNA splicing of DLG1 through interaction with IGF2BP3/RBM14

NONO promotes gallbladder cancer cell proliferation by enhancing oncogenic RNA splicing of DLG1 through interaction with IGF2BP3/RBM14

  • Cancer Lett. 2024 Feb 8:587:216703. doi: 10.1016/j.canlet.2024.216703.
Zi-Yi Yang 1,  Cheng Zhao 2,  Shi-Lei Liu 3,  Li-Jia Pan 4,  Yi-di Zhu 5,  Jing-Wei Zhao 6,  Hua-Kai Wang 7,  Yuan-Yuan Ye 8,  Jing Qiang 9,  Liu-Qing Shi 10,  Jia-Wei Mei 11,  Yang Xie 12,  Wei Gong 13,  Yi-Jun Shu 14,  Ping Dong 15,  Shan-Shan Xiang 16
Affiliations

Affiliations

  • 1 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: alvin_yzy@foxmail.com.
  • 2 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: ZHAOCHENG1996@sjtu.edn.cn.
  • 3 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: 18817818062@163.com.
  • 4 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: panlijia2011@163.com.
  • 5 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: 18721096271@163.com.
  • 6 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: sjtu_zhao@sjtu.edu.cn.
  • 7 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: wanghuakai@outlook.com.
  • 8 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: yeyuanyuan19891028@126.com.
  • 9 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: qiangjing218@163.com.
  • 10 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: lukinstar467@sjtu.edu.cn.
  • 11 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: steve_mei_mjw@hotmail.com.
  • 12 Department of Gastroenterology, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: xie_young@yeah.net.
  • 13 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: gongwei@xinhuamed.com.cn.
  • 14 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: shuyijun@xinhuamed.com.cn.
  • 15 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: dongping@xinhuamed.com.cn.
  • 16 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: xiangshanshan1989@163.com.
PMID: 38341127 DOI: 10.1016/j.canlet.2024.216703
Abstract

Gallbladder Cancer (GBC) is a highly malignant and rapidly progressing tumor of the human biliary system, and there is an urgent need to develop new therapeutic targets and modalities. Non-POU domain-containing octamer-binding protein (NONO) is an RNA-binding protein involved in the regulation of transcription, mRNA splicing, and DNA repair. NONO expression is elevated in multiple tumors and can act as an oncogene to promote tumor progression. Here, we found that NONO was highly expressed in GBC and promoted tumor cells growth. The dysregulation of RNA splicing is a molecular feature of almost all tumor types. Accordingly, mRNA-seq and RIP-seq analysis showed that NONO promoted exon6 skipping in DLG1, forming two isomers (DLG1-FL and DLG1-S). Furthermore, lower Percent-Spliced-In (PSI) values of DLG1 were detected in tumor tissue relative to the paraneoplastic tissue, and were associated with poor patient prognosis. Moreover, DLG1-S and DLG1-FL act as tumor promoters and tumor suppressors, respectively, by regulating the YAP1/JUN pathway. N6-methyladenosine (m6A) is the most common and abundant RNA modification involved in alternative splicing processes. We identified an m6A reader, IGF2BP3, which synergizes with NONO to promote exon6 skipping in DLG1 in an m6A-dependent manner. Furthermore, IP/MS results showed that RBM14 was bound to NONO and interfered with NONO-mediated exon6 skipping of DLG1. In addition, IGF2BP3 disrupted the binding of RBM14 to NONO. Overall, our data elucidate the molecular mechanism by which NONO promotes DLG1 exon skipping, providing a basis for new therapeutic targets in GBC treatment.

Keywords

Alternative splicing; DLG1; Gallbladder cancer; NONO.

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