Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma
Related Experiment Video
Updated: Jul 1, 2025
Development of Compendium for Esophageal Squamous Cell Carcinoma
Published on: April 12, 2024
Wen-Peng Wang1, Dan Shi2, Duo Yun3
1Department of Colorectal Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
Background:
Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with limited treatment options. Deubiquitinases (DUBs) have been confirmed to play a crucial role in the development of malignant tumors. JOSD2 is a DUB involved in controlling protein deubiquitination and influencing critical cellular processes in cancer.
Aim:
To investigate the impact of JOSD2 on the progression of ESCC.
Methods:
Bioinformatic analyses were employed to explore the expression, prognosis, and enriched pathways associated with JOSD2 in ESCC. Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines (KYSE30 and KYSE150). Functional assays, including cell proliferation, colony formation, drug sensitivity, migration, and invasion, were performed, revealing the impact of JOSD2 on ESCC cell lines. JOSD2's role in xenograft tumor growth and drug sensitivity in vivo was also assessed. The proteins that interacted with JOSD2 were identified using mass spectrometry.
Results:
Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues, which was associated with poor prognosis. Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells. JOSD2 knockdown inhibited ESCC cell activity, including proliferation and colony-forming ability. Moreover, JOSD2 knockdown decreased the drug resistance and migration of ESCC cells, while JOSD2 overexpression enhanced these phenotypes. In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC. Mechanistically, JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways. Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2, which identified the four primary proteins that bind to JOSD2, namely USP47, IGKV2D-29, HSP90AB1, and PRMT5.
Conclusion:
JOSD2 plays a crucial role in enhancing the proliferation, migration, and drug resistance of ESCC, suggesting that JOSD2 is a potential therapeutic target in ESCC.
Insights
JOSD2 (J6 specific deubiquitinase 2) promotes esophageal squamous cell carcinoma (ESCC) progression by enhancing cell proliferation, migration, and drug resistance. Targeting JOSD2 may offer a new therapeutic strategy for ESCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Esophageal squamous cell carcinoma (ESCC) is a highly lethal cancer with limited therapeutic strategies.
- Deubiquitinases (DUBs) are critical in cancer development, with JOSD2 (J6 specific deubiquitinase 2) influencing key cellular processes.
- JOSD2's role in ESCC pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the functional role and molecular mechanisms of JOSD2 in ESCC progression.
- To assess the therapeutic potential of targeting JOSD2 in ESCC.
Main Methods:
- Bioinformatic analysis of JOSD2 expression and prognostic value in ESCC.
- In vitro studies using lentiviral transduction to modulate JOSD2 levels in ESCC cell lines (KYSE30, KYSE150).
- Functional assays (proliferation, colony formation, drug sensitivity, migration, invasion) and in vivo xenograft models were employed. Mass spectrometry identified JOSD2-interacting proteins.
Main Results:
- JOSD2 is highly expressed in ESCC tissues and associated with poor prognosis.
- JOSD2 overexpression enhances ESCC cell proliferation, migration, invasion, and drug resistance, while knockdown inhibits these phenotypes.
- JOSD2 promotes tumor growth and drug resistance in vivo, potentially by activating MAPK/ERK and PI3K/AKT pathways. Key interacting proteins include USP47, IGKV2D-29, HSP90AB1, and PRMT5.
Conclusions:
- JOSD2 significantly drives ESCC progression by promoting proliferation, migration, and drug resistance.
- JOSD2 represents a promising therapeutic target for esophageal squamous cell carcinoma.
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