USP20 as a super-enhancer-regulated gene drives T-ALL progression via HIF1A deubiquitination

  • Acta Pharm Sin B. 2025 Sep;15(9):4751-4771. doi: 10.1016/j.apsb.2025.07.003.
Ling Xu  1  2 ,  Zimu Zhang  3 ,  Juanjuan Yu  1 ,  Tongting Ji  1 ,  Jia Cheng  1 ,  Xiaodong Fei  4 ,  Xinran Chu  5 ,  Yanfang Tao  6 ,  Yan Xu  2 ,  Pengju Yang  1 ,  Wenyuan Liu  7 ,  Gen Li  3 ,  Yongping Zhang  5 ,  Yan Li  2 ,  Fenli Zhang  8 ,  Ying Yang  8 ,  Bi Zhou  1  9 ,  Yumeng Wu  1  10 ,  Zhongling Wei  5 ,  Yanling Chen  1 ,  Jianwei Wang  3 ,  Di Wu  3 ,  Xiaolu Li  3 ,  Yang Yang  3 ,  Guanghui Qian  3 ,  Hongli Yin  3 ,  Shuiyan Wu  5 ,  Shuqi Zhang  11 ,  Dan Liu  12 ,  Jun-Jie Fan  5 ,  Lei Shi  13 ,  Xiaodong Wang  14 ,  Shaoyan Hu  5 ,  Jun Lu  5 ,  Jian Pan  3
Affiliations
  • 1. Children's Hospital of Soochow University, Suzhou 215003, China.
  • 2. Department of Pediatrics, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000 China.
  • 3. Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China.
  • 4. Department of Radiology, Children's Hospital of Soochow University, Suzhou 215003, China.
  • 5. Department of Hematology, Children's Hospital of Soochow University, Suzhou 215003, China.
  • 6. Department of Traditional Chinese Medicine, Children's Hospital of Soochow University, Suzhou 215003, China.
  • 7. Department of Pediatrics, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
  • 8. Clinical Medicine, Guizhou Medical University, Guiyang 550000, China.
  • 9. Department of Pediatric, Suzhou Hospital of AnHui Medical University, Suzhou 234000, China.
  • 10. Department of Pediatric, the First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, China.
  • 11. Department of Pediatrics, the First Affiliated Hospital of Wannan Medical College, Wuhu 241002, China.
  • 12. Department of Blood Transfusion, Children's Hospital of Soochow University, Suzhou 215003, China.
  • 13. Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 14. Department of Orthopaedics, Children's Hospital of Soochow University, Suzhou 215003, China.
PMID: 41049757 DOI: 10.1016/j.apsb.2025.07.003
Abstract

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene Ubiquitin-Specific Protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation Sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased Apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit Alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Keywords
GSK2643943A; H3K27ac ChIP-seq; HIF1A; Potential target; Super enhancer; T-ALL; Transcription regulation; USP20.