Epithelial-mesenchymal transition and cancer stem cells: A route to acquired cisplatin resistance through epigenetics in HNSCC

Chemoresistance is associated with tumor recurrence, metastases, and short survival. Cisplatin is one of the most used chemotherapies in cancer treatment, including head and neck squamous cell carcinoma (HNSCC), and many patients develop resistance. Here, we established cell lines resistant to cisplatin to better understand epigenetics and biological differences driving the progression of HNSCC after treatment. Cisplatin resistance was established in CAL-27 and SCC-9 cell lines. Gene expression of HDAC1, HDAC2, SIRT1, MTA1, KAT2B, KAT6A, KAT6B, and BRD4 indicated the cisplatin activates the epigenetic machinery. Increases in tumor aggressiveness were detected by BMI-1 and KI-67 in more resistant cell lines. Changes in cellular shape and epithelial-mesenchymal transition (EMT) activation were also observed. HDAC1 and ZEB1 presented an opposite distribution with down-regulation of HDAC1 and up-regulation of ZEB1 in the course of chemoresistance. Up-regulation of ZEB1 and BMI-1 in patients with HNSCC is also associated with a poor response to therapy. Cancer stem cells (CSC) population increased significantly with chemoresistance. Down-regulation of HDAC1, HDAC2, and SIRT1 and accumulation of Vimentin and ZEB1 were observed in the CSC population. Our results suggest that in the route to cisplatin chemoresistance, epigenetic modifications can be associated with EMT activation and CSC accumulation which originate more aggressive tumors.

Automated summary

Chemoresistance is associated with tumor recurrence, metastases, and short survival. In this study, the researchers established cisplatin-resistant cell lines to investigate the role of epigenetics and biological differences in the progression of head and neck squamous cell carcinoma (HNSCC) after treatment. They found that cisplatin activates the epigenetic machinery and leads to changes in cellular shape and epithelial-mesenchymal transition (EMT). The upregulation of BMI-1 and KI-67 in the more resistant cell lines suggests increased tumor aggressiveness. The researchers also observed that HDAC1 and ZEB1 play opposite roles in the development of chemoresistance, with HDAC1 being down-regulated and ZEB1 being up-regulated. Additionally, the population of cancer stem cells (CSC) increased significantly with chemoresistance, accompanied by the down-regulation of HDAC1, HDAC2, and SIRT1, as well as the accumulation of Vimentin and ZEB1.