Pathology, research and practice · 2026
METTL3 facilitates the malignant progression of prostate cancer by inhibiting GDF15-mediated ferroptosis via a YTHDF1-dependent m6A mechanism.
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Jiang Jun, Li Jinming, Wang Shaoxing, Liu Jiahao, Zuo Shusen
Аннотация
BACKGROUND: Prostate cancer (PCa) represents one of the most common tumors in males. Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor β (TGF-β) family, exhibits elevated expression that correlates with cancer progression (including PCa). The RNA N6-methyladenosine (m6A) modification, an epigenetic regulatory mechanism, has been implicated in oncogenesis and tumor advancement. Therefore, this study aims to delineate the functional role of GDF15 in PCa progression.
METHODS: Differentially expressed genes (DEGs) and GDF15 levels in tumor tissues were analyzed using Gene Expression Omnibus (GEO) and Tumor Immune Estimation Resource (TIMER) database. Gene levels were detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, migration, and sphere-forming abilities were examined using colony formation, transwell, and spheroid formation assays. Reactive-oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and ferrous iron (Fe2 +) levels were examined using corresponding detection kits. Methylation sites of GDF15 were predicted by SRAMP database. Relationship between GDF15 and methyltransferase-like 3/YTH domain family member 1 (METTL3/YTHDF1) was detected using RNA immunoprecipitation (RIP). mRNA stability was analyzed using qRT-PCR. Effects of METTL3 and GDF15 in vivo were confirmed via animal experiment.
RESULTS: GDF15 expression was highly expressed in PCa tissues and cells. Functionally, GDF15 knockdown repressed PCa cell proliferation, migration, and sphere-forming abilities and promoted ferroptosis. Mechanistically, METTL3 combined with YTHDF1 regulated the m6A methylation of GDF15. METTL3 silencing suppressed the malignant biological behaviors of PCa cells via regulating GDF15. In vivo, silencing METTL3 inhibited tumor growth and GDF15 expression.
CONCLUSION: Silencing METTL3 inhibits the malignant biological progression of PCa by mediating GDF15 via a YTHDF1-dependent m6A mechanism. It is important to further research GDF15 and reveal its specific mechanism in PCa.
METHODS: Differentially expressed genes (DEGs) and GDF15 levels in tumor tissues were analyzed using Gene Expression Omnibus (GEO) and Tumor Immune Estimation Resource (TIMER) database. Gene levels were detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, migration, and sphere-forming abilities were examined using colony formation, transwell, and spheroid formation assays. Reactive-oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and ferrous iron (Fe2 +) levels were examined using corresponding detection kits. Methylation sites of GDF15 were predicted by SRAMP database. Relationship between GDF15 and methyltransferase-like 3/YTH domain family member 1 (METTL3/YTHDF1) was detected using RNA immunoprecipitation (RIP). mRNA stability was analyzed using qRT-PCR. Effects of METTL3 and GDF15 in vivo were confirmed via animal experiment.
RESULTS: GDF15 expression was highly expressed in PCa tissues and cells. Functionally, GDF15 knockdown repressed PCa cell proliferation, migration, and sphere-forming abilities and promoted ferroptosis. Mechanistically, METTL3 combined with YTHDF1 regulated the m6A methylation of GDF15. METTL3 silencing suppressed the malignant biological behaviors of PCa cells via regulating GDF15. In vivo, silencing METTL3 inhibited tumor growth and GDF15 expression.
CONCLUSION: Silencing METTL3 inhibits the malignant biological progression of PCa by mediating GDF15 via a YTHDF1-dependent m6A mechanism. It is important to further research GDF15 and reveal its specific mechanism in PCa.