PTBP1 Reduces KLF9 mRNA Stability and Upregulates FUBP1 to Promote Colorectal Cancer Stemness and Cisplatin Resistance

Abstract

The emergence of chemoresistance leads to poor prognosis in colorectal cancer (CRC), and tumor stem cells play an essential role in tumor chemosensitivity. This work delved into the molecular mechanisms by which PTBP1 regulates CRC cell stemness and cisplatin (DDP) resistance. Clinical tissue samples originated from patients with CRC and DDP-resistant CRC. HT-29 and HCT116 cells were treated with DDP to establish DDP-resistant CRC cell lines. CCK-8, clone formation, and sphere formation assays were utilized to detect cell proliferative capacity and stemness, respectively. Chromatin immunoprecipitation, dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down were conducted to validate the interactions among PTBP1, FUBP1, and KLF9. A CRC DDP-resistant nude mouse model was developed for in vivo experiments. PTBP1 and FUBP1 were upregulated, while KLF9 was downregulated in DDP-resistant CRC cells and tissues. Knockdown of FUBP1 abolished CRC cell stemness and DDP chemoresistance in vivo and in vitro. KLF9 interacted with the FUBP1 promoter region to repress FUBP1 transcription. PTBP1 reduced KLF9 mRNA stabilization by binding to KLF9 mRNA, which promoted CRC cell stemness and DDP chemoresistance. PTBP1 reduced the stability of KLF9 mRNA, thereby relieving the transcriptional inhibition of FUBP1 by KLF9, leading to the development of stemness and DDP chemoresistance in CRC cells.