2. Academic Validation
  3. Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex

Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex

  • Cell Oncol (Dordr). 2023 Jul 19. doi: 10.1007/s13402-023-00843-4.
Qiqi Shi 1,  Bo Yu 1,  Yingwen Zhang 1,  Yi Yang 2,  Chenxin Xu 1,  Mingda Zhang 1,  Guoyu Chen 1,  Fei Luo 1,  Bowen Sun 1,  Ru Yang 1,  Yanxin Li 3,  Haizhong Feng 4
Affiliations

Affiliations

  • 1 Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 2 Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 3 Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai Jiao Tong University, Shanghai, 200127, China. liyanxin@scmc.com.cn.
  • 4 Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University, Shanghai, 200127, China. fenghaizhong@sjtu.edu.cn.
PMID: 37466744 DOI: 10.1007/s13402-023-00843-4
Abstract

Purpose: High-risk neuroblastoma (NB) still has an unfavorable prognosis and inducing NB differentiation is a potential strategy in clinical treatment, yet underlying mechanisms are still elusive. Here we identify TRIM24 as an important regulator of NB differentiation.

Methods: Multiple datasets and clinical specimens were analyzed to define the role of TRIM24 in NB. The effects of TRIM24 on differentiation and growth of NB were determined by cell morphology, spheres formation, soft agar assay, and subcutaneous xenograft in nude mice. RNA-Seq and qRT-PCR were used to identify genes and pathways involved. Mass spectrometry and co-immunoprecipitation were used to explore the interaction of proteins.

Results: Trim24 is highly expressed in spontaneous NB in TH-MYCN transgenic mice and clinical NB specimens. It is associated with poor NB differentiation and unfavorable prognostic. Knockout of TRIM24 in neuroblastoma cells promotes cell differentiation, reduces cell stemness, and inhibits colony formation in soft agar and subcutaneous xenograft tumor growth in nude mice. Mechanistically, TRIM24 knockout alters genes and pathways related to neural differentiation and development by suppressing LSD1/CoREST complex formation. Besides, TRIM24 knockout activates the retinoic acid pathway. Targeting TRIM24 in combination with retinoic acid (RA) synergistically promotes NB cell differentiation and inhibits cell viability.

Conclusion: Our findings demonstrate that TRIM24 is critical for NB differentiation and suggest that TRIM24 is a promising therapeutic target in combination with RA in NB differentiation therapy.

Keywords

Differentiation; LSD1; Neuroblastoma; Retinoic acid; TRIM24.

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