KDM5 family of demethylases promotes CD44-mediated chemoresistance in pancreatic adenocarcinomas

TY - JOUR

T1 - KDM5 family of demethylases promotes CD44-mediated chemoresistance in pancreatic adenocarcinomas

AU - Wang, Dan

AU - Zhang, Yingjun

AU - Liao, Zhouning

AU - Ge, Heming

AU - Güngör, Cenap

AU - Li, Yuqiang

N1 - © 2023. Springer Nature Limited.

PY - 2023/10/25

Y1 - 2023/10/25

N2 - A growing body of evidence suggests that the histone demethylase-lysine demethylase 5 (KDM5) family is associated with drug resistance in cancer cells. However, it is still not clear whether KDM5 family members promote chemotherapy resistance in pancreatic ductal adenocarcinomas (PDAC). Comprehensive bioinformatics analysis was performed to investigate the prognostic value, and functional mechanisms of KDM5 family members in PDAC. The effects of KDM5 family members on drug resistance in PDAC cells and the relationship with CD44, as a stem cell marker, were explored by gene knockout and overexpression strategies. Finally, our findings were validated by functional experiments such as cell viability, colony formation and invasion assays. We found that the expression of KDM5A/C was significantly higher in gemcitabine-resistant cells than in sensitive cells, consistent with the analysis of the GSCALite database. The knockdown of KDM5A/C in PDAC cells resulted in diminished drug resistance, less cell colonies and reduced invasiveness, while KDM5A/C overexpression showed the opposite effect. Of note, the expression of KDM5A/C changed accordingly with the knockdown of CD44. In addition, members of the KDM5 family function in a variety of oncogenic pathways, including PI3K/AKT and Epithelial-Mesenchymal Transition. In conclusion, KDM5 family members play an important role in drug resistance and may serve as new biomarkers or potential therapeutic targets in PDAC patients.

AB - A growing body of evidence suggests that the histone demethylase-lysine demethylase 5 (KDM5) family is associated with drug resistance in cancer cells. However, it is still not clear whether KDM5 family members promote chemotherapy resistance in pancreatic ductal adenocarcinomas (PDAC). Comprehensive bioinformatics analysis was performed to investigate the prognostic value, and functional mechanisms of KDM5 family members in PDAC. The effects of KDM5 family members on drug resistance in PDAC cells and the relationship with CD44, as a stem cell marker, were explored by gene knockout and overexpression strategies. Finally, our findings were validated by functional experiments such as cell viability, colony formation and invasion assays. We found that the expression of KDM5A/C was significantly higher in gemcitabine-resistant cells than in sensitive cells, consistent with the analysis of the GSCALite database. The knockdown of KDM5A/C in PDAC cells resulted in diminished drug resistance, less cell colonies and reduced invasiveness, while KDM5A/C overexpression showed the opposite effect. Of note, the expression of KDM5A/C changed accordingly with the knockdown of CD44. In addition, members of the KDM5 family function in a variety of oncogenic pathways, including PI3K/AKT and Epithelial-Mesenchymal Transition. In conclusion, KDM5 family members play an important role in drug resistance and may serve as new biomarkers or potential therapeutic targets in PDAC patients.

KW - Humans

KW - Pancreatic Neoplasms/drug therapy

KW - Adenocarcinoma/drug therapy

KW - Drug Resistance, Neoplasm/genetics

KW - Phosphatidylinositol 3-Kinases

KW - Carcinoma, Pancreatic Ductal/drug therapy

KW - Cell Line, Tumor

KW - Retinoblastoma-Binding Protein 2

KW - Hyaluronan Receptors/genetics

U2 - 10.1038/s41598-023-44536-2

DO - 10.1038/s41598-023-44536-2

M3 - SCORING: Journal article

C2 - 37880235

VL - 13

SP - 18250

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -