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

xlomafota13 shared this article with you from Inoreader The transcription co-factor JAB1/COPS5, serves as a potential oncogenic hub of human chondrosarcoma cells <em>in vitro</em> Via American Journal of Cancer Research Am J Cancer Res. 2021 Oct 15;11(10):5063-5075. eCollection 2021. ABSTRACT Chondrosarcoma (CS) is the second most common skeletal malignancy in humans. High-grade CS is aggressive and extremely resistant to chemo- and radio-therapies. The lack of effective treatment options warrants the development of novel therapies. The evolutionarily conserved transcriptional co-factor JAB1 (also known as COPS5/CSN5) has emerged as a novel regulator of tumorigenesis. JAB1 overexpression occurs in many common cancers and is associated with poor prognosis. However, the role of JAB1 in CS pathogenesis was completely unknown. To study JAB1's function in CS, we performed shRNA knockdown (KD) of JAB1 in two high-grade human CS cell lines, SW1353 and Hs819.T, and observed significantly decreased proliferation and colony formations, and increased apoptosis in both CS cell lines upon JAB1-KD. Interestingly, we found that endogenous JAB1 interacted with endogenous SOX9, a potent oncogene and a master regulator of skeletogenesis, in chondrosarcoma cells, but not in primary chondrocytes. JAB1 also binds to the same SOX9-mediated chondrocyte-specific enhancer elements in CS cells. Furthermore, we found that a recently developed, novel, potent, and JAB1-specific small molecule inhibitor, CSN5i-3, can significantly increase apoptosis, drastically alter the activities of several signaling pathways, and modulates the expression of specific Cullin-ring-ligases (CRLs) in CS cells. Finally, our RNA-sequencing analysis in JAB1-KD CS cells identified a total of 2945 differentially expressed genes. Gene set enrichment analysis revealed that JAB1 regulates several essential pathways such as DNA damage response and cell cycle regulation. In conclusion, our study showed that JAB1 might regulate a distinct pro-tumorigenic regulatory network to promote chondrosarcoma pathogenesis. PMID:34765312 | PMC:PMC8569363 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.