2. Academic Validation
  3. USP20 as a super-enhancer-regulated gene drives T-ALL progression via HIF1A deubiquitination

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

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.

Figures