p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino
Summary: Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formati...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721007051 |
| _version_ | 1819008978029379584 |
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| author | Christina B. Marney Erik S. Anderson Mutayyaba Adnan Kai-Lin Peng Ya Hu Nils Weinhold Adam M. Schmitt |
| author_facet | Christina B. Marney Erik S. Anderson Mutayyaba Adnan Kai-Lin Peng Ya Hu Nils Weinhold Adam M. Schmitt |
| author_sort | Christina B. Marney |
| collection | DOAJ |
| description | Summary: Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression. |
| first_indexed | 2024-12-21T00:49:03Z |
| format | Article |
| id | doaj.art-bd01eb6f8706493eb1d6b382e933b3a7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T00:49:03Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-bd01eb6f8706493eb1d6b382e933b3a72022-12-21T19:21:26ZengElsevierCell Reports2211-12472021-06-013513109329p53-intact cancers escape tumor suppression through loss of long noncoding RNA DinoChristina B. Marney0Erik S. Anderson1Mutayyaba Adnan2Kai-Lin Peng3Ya Hu4Nils Weinhold5Adam M. Schmitt6Division of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USADivision of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USADivision of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USADivision of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USADivision of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USADivision of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USADivision of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USA; Corresponding authorSummary: Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression.http://www.sciencedirect.com/science/article/pii/S2211124721007051DINOlong noncoding RNAp53tumor suppressioncancerDNA methylation |
| spellingShingle | Christina B. Marney Erik S. Anderson Mutayyaba Adnan Kai-Lin Peng Ya Hu Nils Weinhold Adam M. Schmitt p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino Cell Reports DINO long noncoding RNA p53 tumor suppression cancer DNA methylation |
| title | p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino |
| title_full | p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino |
| title_fullStr | p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino |
| title_full_unstemmed | p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino |
| title_short | p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino |
| title_sort | p53 intact cancers escape tumor suppression through loss of long noncoding rna dino |
| topic | DINO long noncoding RNA p53 tumor suppression cancer DNA methylation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721007051 |
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