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

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.

SUBMITTER: Mamidi M

PROVIDER: S-EPMC8569363 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The TBX2 transcription factor plays critical roles during embryonic development and it is overexpressed in several cancers, where it contributes to key oncogenic processes including the promotion of proliferation and bypass of senescence. Importantly, based on compelling biological evidences, TBX2 has been considered as a potential target for new anticancer therapies. There has therefore been a substantial interest to identify molecules with TBX2-modulatory activity, but no such substance has been found to date. Here, we adopt a targeted approach based on a reverse-affinity procedure to identify the ability of chromomycins A5 (CA5) and A6 (CA6) to interact with TBX2. Briefly, a TBX2-DNA-binding domain recombinant protein was N-terminally linked to a resin, which in turn, was incubated with either CA5 or CA6. After elution, bound material was analyzed by UPLC-MS and CA5 was recovered from TBX2-loaded resins. To confirm and quantify the affinity (KD) between the compounds and TBX2, microscale thermophoresis analysis was performed. CA5 and CA6 modified the thermophoretic behavior of TBX2, with a KD in micromolar range. To begin to understand whether these compounds exerted their anti-cancer activity through binding TBX2, we next analyzed their cytotoxicity in TBX2 expressing breast carcinoma, melanoma and rhabdomyosarcoma cells. The results show that CA5 was consistently more potent than CA6 in all tested cell lines with IC50 values in the nM range. Of the cancer cell types tested, the melanoma cells were most sensitive. The knockdown of TBX2 in 501mel melanoma cells increased their sensitivity to CA5 by up to 5 times. Furthermore, inducible expression of TBX2 in 501mel cells genetically engineered to express TBX2 in the presence of doxycycline, were less sensitive to CA5 than the control cells. Together, the data presented in this study suggest that, in addition to its already recognized DNA-binding properties, CA5 may be binding the transcription factor TBX2, and it can contribute to its cytotoxic activity.

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

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