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

Abstract

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.

Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma

“…More importantly, our scATAC sequencing revealed that cluster 1 displayed enriched peaks with transcriptional motifs containing stem-cell like features, EMT surface markers, and high expression of KNC genes such as AKR1C1, AKR1C2, AKR1C3 and SPP1. These findings are supported by a recent study which demonstrated that EMT and cancer stem cells lead to acquired CDDP resistance and tumor recurrence through epigenetic changes in HNSCC (57). Although our data suggest that a unique epigenomic reprogramming contributes to evolution of CDDP-resistant clones in HNSCC, it remains unclear how this occurs and therefore further in vitro and in vivo molecular characterization is necessary to understand this mechanistic link.…”

Isothiocyanates (ITCs) 1-(Isothiocyanatomethyl)-4-phenylbenzene and 1-Isothiocyanato-3,5-bis(trifluoromethyl)benzene—Aldehyde Dehydrogenase (ALDH) Inhibitors, Decreases Cisplatin Tolerance and Migratory Ability of NSCLC

“…Furthermore, in our A549CisR cell line, cisplatin resistance manifests as ongoing EMT, indicated by upregulation of N-cadherin and repression of E-cadherin, which substantially increased migratory potential. Previous studies have also noted a similar co-existence between cisplatin resistance and EMT induction [ 72 , 74 ]. Importantly, our derived A549CisR cell line, representing an EMT phenotype, demonstrated ABCC1 and ABCC4 upregulation and ABCG2 downregulation; this relationship was observed for GSE108214, while ABCG2 repression has also been noted in advanced colorectal cancer cells undergoing EMT and patient samples [ 57 ].…”

Up‐regulation of TNF‐alpha/NFkB/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma

“…(Lima de Oliveira et al, 2022). Our results suggest that the upregulation of HDAC1 and SIRT1 in the CisR cell lines can be mediated by the TNF-alpha/NFkB signaling.…”