METTL3 enhances esophageal squamous cell carcinoma progression by suppressing ferroptosis through the PBX3/CA9 cascade
Year: 2025
Type: article
Abstract: Background N 6 -methyladenosine (m 6 A) modification controls various processes during tumorigenesis. Although METTL3 functions as a pro-tumorigenic driver in esophageal squamous cell carcinoma (ESCC), its mechanisms are largely unknown. Methods mRNA expression was detected by quantitative PCR , and protein expression was assessed by immunoblotting . Cell motility , invasiveness, and apoptosis were analyzed by wound-healing assay, transwell assay and flow cytometry, respectively. Cell ferroptosis was assessed by detecting the contents of ROS , MDA and Fe 2+ . The METTL3/PBX3 and PBX3/CA9 relationships were validated by luciferase , MeRIP or ChIP assay. The effect of METTL3 on tumor growth was tested by xenograft studies. Results METTL3 was enhanced in ESCC tumors and cells, and its deficiency suppressed ESCC cell migration and invasion and promoted cell apoptosis and ferroptosis . Additionally, METTL3 deficiency caused growth inhibition of ESCC xenografts in vivo . METTL3 enhanced m6A modification of PBX3 mRNA. PBX3 was identified as a mediator of METTL3 function in modulating ESCC cell phenotypes. PBX3 promoted CA9 transcription, and METTL3 positively regulated CA9 through PBX3. PBX3 deficiency impeded ESCC cell migration and invasion and enhanced cell apoptosis and ferroptosis by downregulating CA9 . Conclusion Our study elucidates a novel mechanism, the METTL3/PBX3/CA9 cascade, underlying the oncogenic activity of METTL3 in ESCC. The novel cascade may represent the potential target for ESCC therapy in the future.
Authors: Lingxia Yang, Chang'e Ding, Mengjie Tuo, Tiandong Chu, Ping Liu
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,780
Award: G3669321462
OpenAlex ID: W4407959462