2. Academic Validation
  3. CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma

  • Cancer Lett. 2024 Apr 16:591:216882. doi: 10.1016/j.canlet.2024.216882.
Ran Zhuo 1,  Zimu Zhang 2,  Yanling Chen 2,  Gen Li 2,  Shibei Du 2,  Xinyi Guo 3,  Randong Yang 1,  Yanfang Tao 2,  Xiaolu Li 2,  Fang Fang 2,  Yi Xie 2,  Di Wu 2,  Yang Yang 2,  Chun Yang 2,  Hongli Yin 2,  Guanghui Qian 2,  Hairong Wang 2,  Juanjuan Yu 2,  Siqi Jia 2,  Frank Zhu 4,  Chenxi Feng 2,  Jianwei Wang 2,  Yunyun Xu 2,  Zhiheng Li 2,  Lei Shi 5,  Xiaodong Wang 6,  Jian Pan 7,  Jian Wang 8
Affiliations

Affiliations

  • 1 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215003, China; Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, Jiangsu, 215025, China.
  • 2 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215003, China.
  • 3 Department of Infection Management, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, China.
  • 4 Division of Hematology, Department of Internal Medicine, The Ohio State University, China.
  • 5 Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, China.
  • 6 Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, Jiangsu, 215025, China.
  • 7 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215003, China. Electronic address: panjian2008@163.com.
  • 8 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215003, China; Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, Jiangsu, 215025, China. Electronic address: wj196312@vip163.com.
PMID: 38636893 DOI: 10.1016/j.canlet.2024.216882
Abstract

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Keywords

CDK5RAP3; ER-Phagy; Master TFs; Neuroblastoma; Super-enhancer.

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