Project description:We previously reported that an aggressive subpopulation of highly tumorigenic, drug-resistant bladder cancer cells can arise from the bulk tumor cells without mutational events and that this phenotypic plasticity is driven at least in part by epigenetic mechanisms. In the current work, we analyzed the chromatin accessibility of enhancers to identify transcription factors that contribute to this transition to a drug-resistant state. Comparing the drug resistant side population (SP) cells and the less drug resistant non-side population (NSP) cells in bladder cancer cells, we identified differential accessible enhancers and differentially expressed genes. Transcription factor motif analysis showed that FOX family motif was enriched in accessible enhancers near SP-overexpressed genes. Among FOX family transcription factors, FOXC1 was the only overexpressed transcription factor, and it was also the most significantly overexpressed gene in SP cells. FOXC1 ChIP-seq confirmed that FOXC1 binding sites are more accessible in SP cells and showed a significantly more FOXC1 binding near the overexpressed genes in SP cells. When the FOXC1 is knocked out, bladder cancer cells exhibit decreased cisplatin resistance and less percentage of SP cells. This change in cisplatin resistance is partially related to the FOXC1-driven expression of ABCB1 gene. In summary, our observations suggest that differential expression and enhancer binding of FOXC1 promotes the previously observed, mutation-independent shift towards cisplatin resistance in bladder cancer.
Project description:We previously reported that an aggressive subpopulation of highly tumorigenic, drug-resistant bladder cancer cells can arise from the bulk tumor cells without mutational events and that this phenotypic plasticity is driven at least in part by epigenetic mechanisms. In the current work, we analyzed the chromatin accessibility of enhancers to identify transcription factors that contribute to this transition to a drug-resistant state. Comparing the drug resistant side population (SP) cells and the less drug resistant non-side population (NSP) cells in bladder cancer cells, we identified differential accessible enhancers and differentially expressed genes. Transcription factor motif analysis showed that FOX family motif was enriched in accessible enhancers near SP-overexpressed genes. Among FOX family transcription factors, FOXC1 was the only overexpressed transcription factor, and it was also the most significantly overexpressed gene in SP cells. FOXC1 ChIP-seq confirmed that FOXC1 binding sites are more accessible in SP cells and showed a significantly more FOXC1 binding near the overexpressed genes in SP cells. When the FOXC1 is knocked out, bladder cancer cells exhibit decreased cisplatin resistance and less percentage of SP cells. This change in cisplatin resistance is partially related to the FOXC1-driven expression of ABCB1 gene. In summary, our observations suggest that differential expression and enhancer binding of FOXC1 promotes the previously observed, mutation-independent shift towards cisplatin resistance in bladder cancer.
Project description:We previously reported that an aggressive subpopulation of highly tumorigenic, drug-resistant bladder cancer cells can arise from the bulk tumor cells without mutational events and that this phenotypic plasticity is driven at least in part by epigenetic mechanisms. In the current work, we analyzed the chromatin accessibility of enhancers to identify transcription factors that contribute to this transition to a drug-resistant state. Comparing the drug resistant side population (SP) cells and the less drug resistant non-side population (NSP) cells in bladder cancer cells, we identified differential accessible enhancers and differentially expressed genes. Transcription factor motif analysis showed that FOX family motif was enriched in accessible enhancers near SP-overexpressed genes. Among FOX family transcription factors, FOXC1 was the only overexpressed transcription factor, and it was also the most significantly overexpressed gene in SP cells. FOXC1 ChIP-seq confirmed that FOXC1 binding sites are more accessible in SP cells and showed a significantly more FOXC1 binding near the overexpressed genes in SP cells. When the FOXC1 is knocked out, bladder cancer cells exhibit decreased cisplatin resistance and less percentage of SP cells. This change in cisplatin resistance is partially related to the FOXC1-driven expression of ABCB1 gene. In summary, our observations suggest that differential expression and enhancer binding of FOXC1 promotes the previously observed, mutation-independent shift towards cisplatin resistance in bladder cancer.
