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Войти в исследования Cellular & molecular biology letters · 2026
piR-26681 suppresses ovarian cancer progression by enhancing METTL3/METTL14-mediated m6A modification of FBXO16 and impairing DNA repair via MORF4L1 degradation.
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Wang Jie-Lin, Wu Qing-Hua, Yuan Jing, Bao Hai-Juan, Huang Xiang-Chun, Cheng Jia-Chen, Zhao Yang, Chen Shuo
Аннотация
BACKGROUND: Survival rates for ovarian cancer drop sharply at late-stages due to late diagnosis. Although PARP inhibitors are effective in homologous recombination-deficient (HRD) tumors, their efficacy in homologous recombination (HR)-proficient ovarian cancer remains limited, highlighting the need for novel molecular targets to inhibit tumor progression and improve patient outcomes.
METHODS: Differentially expressed piRNAs were screened using ovarian cancer tissues from early- and advanced-stage patients. Functional studies were performed in ovarian cancer cell lines, xenograft models, and patient-derived organoids. Molecular mechanisms were investigated using RNA pulldown, RNA immunoprecipitation, MeRIP-seq, ubiquitination assays, and DNA damage analyses.
RESULTS: We identified piR-26681 as a piRNA significantly downregulated in advanced-stage ovarian cancer and associated with favorable prognosis. Functional assays demonstrated that piR-26681 suppressed ovarian cancer progression in cell lines, xenograft mouse models, and patient-derived organoids. Mechanistically, piR-26681 directly interacted with METTL3 and METTL14, enhancing their interaction, reducing their ubiquitination, and thereby increasing their protein stability. This stabilization promoted global m6A methylation in ovarian cancer cells. Increased m6A modification subsequently enhanced the stability of FBXO16 mRNA through the m6A reader IGF2BP2, leading to elevated FBXO16 expression. As an E3 ubiquitin ligase, FBXO16 further mediated the ubiquitination and degradation of MORF4L1, a key regulator of homologous recombination repair. Loss of MORF4L1 impaired HR repair, increased DNA damage accumulation, and sensitized ovarian cancer cells to the PARP inhibitor niraparib.
CONCLUSIONS: Our study identifies a novel piR-26681-METTL3/METTL14-FBXO16-MORF4L1 regulatory axis that impairs DNA repair and suppresses ovarian cancer progression. piR-26681 represents a promising therapeutic target for sensitizing HR-proficient ovarian cancers to DNA-damaging therapies.
METHODS: Differentially expressed piRNAs were screened using ovarian cancer tissues from early- and advanced-stage patients. Functional studies were performed in ovarian cancer cell lines, xenograft models, and patient-derived organoids. Molecular mechanisms were investigated using RNA pulldown, RNA immunoprecipitation, MeRIP-seq, ubiquitination assays, and DNA damage analyses.
RESULTS: We identified piR-26681 as a piRNA significantly downregulated in advanced-stage ovarian cancer and associated with favorable prognosis. Functional assays demonstrated that piR-26681 suppressed ovarian cancer progression in cell lines, xenograft mouse models, and patient-derived organoids. Mechanistically, piR-26681 directly interacted with METTL3 and METTL14, enhancing their interaction, reducing their ubiquitination, and thereby increasing their protein stability. This stabilization promoted global m6A methylation in ovarian cancer cells. Increased m6A modification subsequently enhanced the stability of FBXO16 mRNA through the m6A reader IGF2BP2, leading to elevated FBXO16 expression. As an E3 ubiquitin ligase, FBXO16 further mediated the ubiquitination and degradation of MORF4L1, a key regulator of homologous recombination repair. Loss of MORF4L1 impaired HR repair, increased DNA damage accumulation, and sensitized ovarian cancer cells to the PARP inhibitor niraparib.
CONCLUSIONS: Our study identifies a novel piR-26681-METTL3/METTL14-FBXO16-MORF4L1 regulatory axis that impairs DNA repair and suppresses ovarian cancer progression. piR-26681 represents a promising therapeutic target for sensitizing HR-proficient ovarian cancers to DNA-damaging therapies.