USP20 as a super-enhancer-regulated gene drives T-ALL progression via HIF1A deubiquitination
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 (<i>USP20</i>) 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 <i>USP20</i> as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that <i>USP20</i> is specifically highly expressed in T-ALL. Knocking down <i>USP20</i> with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. <i>In vivo</i> studies showed that <i>USP20</i> 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.
Authors
- Guanghui Qian (ORCID: https://orcid.org/0009-0005-5552-9125)
- Shaoyan Hu (ORCID: https://orcid.org/0000-0002-5183-2259)
- Yanfang Tao
- Xinran Chu
- Fenli Zhang
- Ying Yang (ORCID: https://orcid.org/0000-0002-8104-5985)
- Pengju Yang
- Jian Pan (ORCID: https://orcid.org/0000-0002-0292-5141)
- Shuiyan Wu (ORCID: https://orcid.org/0000-0002-8963-5082)
- Zhongling Wei (ORCID: https://orcid.org/0000-0002-2763-0964)
- Junjie Fan (ORCID: https://orcid.org/0009-0004-5697-0628)
- Zi-Mu Zhang (ORCID: https://orcid.org/0000-0002-7791-4252)
- Xiaodong Fei
- Gen Li (ORCID: https://orcid.org/0000-0003-0087-7796)
- Yan Li (ORCID: https://orcid.org/0000-0002-4841-9543)
- Xiaolu Li (ORCID: https://orcid.org/0009-0009-4673-2016)
- Xiaodong Wang (ORCID: https://orcid.org/0000-0001-9885-356X)
- Yang Yang (ORCID: https://orcid.org/0000-0001-6088-5435)
- Jianwei Wang (ORCID: https://orcid.org/0000-0002-2832-4205)
- Wenyuan Liu (ORCID: https://orcid.org/0000-0002-2536-9416)
- Yanling Chen (ORCID: https://orcid.org/0000-0002-6387-8561)
- Di Wu (ORCID: https://orcid.org/0000-0001-5623-5819)
- Yongping Zhang (ORCID: https://orcid.org/0000-0001-5090-9173)
- Dan Liu (ORCID: https://orcid.org/0009-0004-0858-0561)
- Jun Lu (ORCID: https://orcid.org/0000-0001-5412-2132)
- Lei Shi (ORCID: https://orcid.org/0000-0003-3583-4649)
- Zhou Bi
- Yumeng Wu (ORCID: https://orcid.org/0000-0001-7160-3210)
- Shuqi Zhang (ORCID: https://orcid.org/0000-0002-1709-8505)
- Tongting Ji
- Hongli Yin
- Juanjuan Yu
- Ling Xu (ORCID: https://orcid.org/0000-0003-0749-6195)
- Jia Cheng
- Xu Yan
Institutions
- Wannan Medical College (CN)
- Guiyang Medical University (CN)
- China Pharmaceutical University (CN)
- Bengbu Medical College (CN)
- Xuzhou Medical College (CN)
- Anhui Medical University (CN)
- Soochow University (CN)
- Affiliated Hospital of Xuzhou Medical College (CN)
- Suzhou Municipal Hospital (CN)
- Suzhou Traditional Chinese Medicine Hospital (CN)
- Second Affiliated Hospital of Anhui Medical University (CN)
- First Affiliated Hospital of Bengbu Medical College (CN)
- Children's Hospital of Suzhou University (CN)
- First Affiliated Hospital of Wannan Medical College (CN)
Publication Details
- Journal
- Acta Pharmaceutica Sinica B
- Published
- 2025-07-05
- DOI
- https://doi.org/10.1016/j.apsb.2025.07.003
- Citations
- 4
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 7.51