Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer
Yunhua Liu, … , Guang Ji, Xiongbin Lu
Yunhua Liu, … , Guang Ji, Xiongbin Lu
Published April 12, 2018
Citation Information: J Clin Invest. 2018;128(7):2951-2965. https://doi.org/10.1172/JCI98727.
View: Text | PDF
Research Article Oncology

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

  • Text
  • PDF
Abstract

A synthetic lethality–based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the “essential lethality” arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.

Authors

Yunhua Liu, Hanchen Xu, Kevin Van der Jeught, Yujing Li, Sheng Liu, Lu Zhang, Yuanzhang Fang, Xinna Zhang, Milan Radovich, Bryan P. Schneider, Xiaoming He, Cheng Huang, Chi Zhang, Jun Wan, Guang Ji, Xiongbin Lu

×

Figure 2

Depletion of SA1 inhibits the growth of SA2-mutated cells in vitro.

Options: View larger image (or click on image) Download as PowerPoint
Depletion of SA1 inhibits the growth of SA2-mutated cells in vitro.
(A a...
(A and B) Cell growth curve, based on crystal violet staining, of EWS (A) and BUC (B) cell lines expressing Dox-inducible control shRNA (shNT) or SA1-specific shRNA (shSA1). (C) Fraction of apoptotic cells in the SA2-intact (TC71, RT4) and SA2-mutated (TC32, UC3) cell lines expressing Dox-induced shSA1 for 4 days. *P < 0.05; **P < 0.01. One-way ANOVA followed by Tukey’s t test (A and B) and unpaired 2-tailed t test (C) were performed to compare different groups. Data are presented as mean ± SD and are representative of 3 independent experiments. Ctrl, control.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts