The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21
Abstract Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) are promising targets or agents for the treatment of human cancers. Most liver-specific lncRNAs exhibit loss of expression and act as tumor suppressors in liver cancer. Modulating the expression of these liver-specific ln...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07401-w |
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| author | Yifei He Hongquan Li Qili Shi Yanfang Liu Qiaochu Pan Xianghuo He |
| author_facet | Yifei He Hongquan Li Qili Shi Yanfang Liu Qiaochu Pan Xianghuo He |
| author_sort | Yifei He |
| collection | DOAJ |
| description | Abstract Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) are promising targets or agents for the treatment of human cancers. Most liver-specific lncRNAs exhibit loss of expression and act as tumor suppressors in liver cancer. Modulating the expression of these liver-specific lncRNAs is a potential approach for lncRNA-based gene therapy for hepatocellular carcinoma (HCC). Here, we report that the expression of the liver-specific lncRNA FAM99B is significantly decreased in HCC tissues and that FAM99B suppresses HCC cell proliferation and metastasis both in vitro and in vivo. FAM99B promotes the nuclear export of DDX21 through XPO1, leading to further cleavage of DDX21 by caspase3/6 in the cytoplasm. FAM99B inhibits ribosome biogenesis by inhibiting ribosomal RNA (rRNA) processing and RPS29/RPL38 transcription, thereby reducing global protein synthesis through downregulation of DDX21 in HCC cells. Interestingly, the FAM99B65-146 truncation exhibits tumor-suppressive effects in vivo and in vitro. Moreover, GalNAc-conjugated FAM99B65-146 inhibits the growth and metastasis of orthotopic HCC xenografts, providing a new strategy for the treatment of HCC. This is the first report of the use of a lncRNA as an agent rather than a target in tumor treatment. Graphical illustration of the mechanism of FAM99B in HCC. |
| format | Article |
| id | doaj-art-5562f347eda746f087bed1b909e62dd6 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-5562f347eda746f087bed1b909e62dd62025-08-20T03:09:20ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111510.1038/s41419-025-07401-wThe liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21Yifei He0Hongquan Li1Qili Shi2Yanfang Liu3Qiaochu Pan4Xianghuo He5Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan UniversityAbstract Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) are promising targets or agents for the treatment of human cancers. Most liver-specific lncRNAs exhibit loss of expression and act as tumor suppressors in liver cancer. Modulating the expression of these liver-specific lncRNAs is a potential approach for lncRNA-based gene therapy for hepatocellular carcinoma (HCC). Here, we report that the expression of the liver-specific lncRNA FAM99B is significantly decreased in HCC tissues and that FAM99B suppresses HCC cell proliferation and metastasis both in vitro and in vivo. FAM99B promotes the nuclear export of DDX21 through XPO1, leading to further cleavage of DDX21 by caspase3/6 in the cytoplasm. FAM99B inhibits ribosome biogenesis by inhibiting ribosomal RNA (rRNA) processing and RPS29/RPL38 transcription, thereby reducing global protein synthesis through downregulation of DDX21 in HCC cells. Interestingly, the FAM99B65-146 truncation exhibits tumor-suppressive effects in vivo and in vitro. Moreover, GalNAc-conjugated FAM99B65-146 inhibits the growth and metastasis of orthotopic HCC xenografts, providing a new strategy for the treatment of HCC. This is the first report of the use of a lncRNA as an agent rather than a target in tumor treatment. Graphical illustration of the mechanism of FAM99B in HCC.https://doi.org/10.1038/s41419-025-07401-w |
| spellingShingle | Yifei He Hongquan Li Qili Shi Yanfang Liu Qiaochu Pan Xianghuo He The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21 Cell Death and Disease |
| title | The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21 |
| title_full | The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21 |
| title_fullStr | The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21 |
| title_full_unstemmed | The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21 |
| title_short | The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21 |
| title_sort | liver specific long noncoding rna fam99b inhibits ribosome biogenesis and cancer progression through cleavage of dead box helicase 21 |
| url | https://doi.org/10.1038/s41419-025-07401-w |
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