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Updated: May 9, 2026
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
RNA interference against cancer/testis genes identifies dual specificity phosphatase 21 as a potential therapeutic
Qing Deng1, Kun-Yu Li, Hui Chen
1Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Unlabelled:
Cancer/testis (CT) antigens have been considered therapeutic targets for treating cancers. However, a central question is whether their expression contributes to tumorigenesis or if they are functionally irrelevant by-products derived from the process of cellular transformation. In any case, these CT antigens are essential for cancer cell survival and may serve as potential therapeutic targets. Recently, the cell-based RNA interference (RNAi) screen has proven to be a powerful approach for identifying potential therapeutic targets. In this study we sought to identify new CT antigens as potential therapeutic targets for human hepatocellular carcinoma (HCC), and 179 potential CT genes on the X chromosome were screened through a bioinformatics analysis of gene expression profiles. Then an RNAi screen against these potential CT genes identified nine that were required for sustaining the survival of Focus and PLC/PRF/5 cells. Among the nine genes, the physiologically testis-restricted dual specificity phosphatase 21 (DUSP21) encoding a dual specificity phosphatase was up-regulated in 39 (33%) of 118 human HCC specimens. Ectopic DUSP21 had no obvious impact on proliferation and colony formation in HCC cells. However, DUSP21 silencing significantly suppressed cell proliferation, colony formation, and in vivo tumorigenicity in HCC cells. The administration of adenovirus-mediated RNAi and an atelocollagen/siRNA mixture against endogenous DUSP21 significantly suppressed xenograft HCC tumors in mice. Further investigations showed that DUSP21 knockdown led to arrest of the cell cycle in G1 phase, cell senescence, and expression changes of some factors with functions in the cell cycle and/or senescence. Furthermore, the antiproliferative role of DUSP21 knockdown is through activation of p38 mitogen-activated protein kinase in HCC.
Conclusion:
DUSP21 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment.
Insights
Dual specificity phosphatase 21 (DUSP21) is crucial for hepatocellular carcinoma (HCC) cell survival and proliferation. Targeting DUSP21 shows promise as a new therapeutic strategy for treating HCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer/testis (CT) antigens are potential therapeutic targets in oncology.
- Identifying novel CT antigens is crucial for developing new cancer treatments.
- RNA interference (RNAi) screening is an effective method for target identification.
Purpose of the Study:
- To identify novel CT antigens as potential therapeutic targets for hepatocellular carcinoma (HCC).
- To investigate the role of Dual Specificity Phosphatase 21 (DUSP21) in HCC progression and survival.
Main Methods:
- Bioinformatic analysis of gene expression profiles for 179 X-chromosome CT genes.
- RNAi screening to identify genes essential for HCC cell survival.
- In vitro assays (proliferation, colony formation) and in vivo xenograft models in mice.
- Cell cycle analysis, senescence assays, and Western blotting to elucidate DUSP21's mechanism of action.
Main Results:
- Nine CT genes were identified as essential for HCC cell survival.
- DUSP21, a testis-restricted phosphatase, was upregulated in 33% of HCC specimens.
- DUSP21 silencing significantly suppressed HCC cell proliferation, colony formation, and in vivo tumor growth.
- DUSP21 knockdown induced G1 cell cycle arrest and senescence, mediated by p38 MAPK activation.
Conclusions:
- DUSP21 plays a critical role in sustaining HCC cell proliferation and tumorigenicity.
- DUSP21 is a promising therapeutic target for HCC treatment.
- Targeting DUSP21 may offer a novel strategy for hepatocellular carcinoma therapy.
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