The transcription co-factor JAB1/COPS5, serves as a potential oncogenic hub of human chondrosarcoma cells in vitro

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Chondrosarcoma (CS) is a common skeletal cancer with limited treatment options, particularly for high-grade aggressive forms.
• JAB1 (COPS5/CSN5), a transcriptional co-factor, is implicated in tumorigenesis across various cancers but its role in CS was uncharacterized.
• Understanding novel regulators like JAB1 is crucial for developing new therapeutic strategies for CS.

Purpose of the Study:

• To investigate the role of JAB1 in the pathogenesis of high-grade chondrosarcoma.
• To identify potential therapeutic targets and agents for CS based on JAB1 function.
• To elucidate the molecular mechanisms by which JAB1 contributes to CS development.

Main Methods:

• Knockdown of JAB1 using shRNA in human high-grade CS cell lines (SW1353, Hs819.T).
• Analysis of JAB1-SOX9 interaction and binding to enhancer elements using co-immunoprecipitation and ChIP assays.
• Treatment with a novel JAB1-specific inhibitor (CSN5i-3) and assessment of cellular effects.
• RNA-sequencing and gene set enrichment analysis to identify regulated pathways.

Main Results:

• JAB1 knockdown significantly reduced proliferation and colony formation while increasing apoptosis in CS cells.
• JAB1 was found to interact with the oncogene SOX9 in CS cells and bind to SOX9-regulated enhancers.
• The JAB1 inhibitor CSN5i-3 induced apoptosis, altered signaling pathways, and modulated Cullin-ring-ligase expression in CS cells.
• RNA-seq identified 2945 differentially expressed genes upon JAB1 knockdown, implicating JAB1 in DNA damage response and cell cycle regulation.

Conclusions:

• JAB1 plays a significant pro-tumorigenic role in chondrosarcoma pathogenesis.
• JAB1 interacts with SOX9 and regulates critical oncogenic pathways in CS.
• Targeting JAB1 with inhibitors like CSN5i-3 represents a promising therapeutic strategy for chondrosarcoma.