Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing
Summary: Comprehensive sequencing approaches have allowed for the identification of the most frequent contributors to cancer, known as drivers. They have also revealed a class of mutations in understudied, infrequently altered genes, referred to as “long tail” (LT) drivers. A key challenge has been...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719311088 |
| _version_ | 1818032635793899520 |
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| author | Jessica S. Elman Thomas K. Ni Kristen E. Mengwasser Dexter Jin Ania Wronski Stephen J. Elledge Charlotte Kuperwasser |
| author_facet | Jessica S. Elman Thomas K. Ni Kristen E. Mengwasser Dexter Jin Ania Wronski Stephen J. Elledge Charlotte Kuperwasser |
| author_sort | Jessica S. Elman |
| collection | DOAJ |
| description | Summary: Comprehensive sequencing approaches have allowed for the identification of the most frequent contributors to cancer, known as drivers. They have also revealed a class of mutations in understudied, infrequently altered genes, referred to as “long tail” (LT) drivers. A key challenge has been to find clinically relevant LT drivers and to understand how they cooperate to drive disease. Here, we identified far upstream binding protein 1 (FUBP1) as an LT driver using an in vivo CRISPR screen. FUBP1 cooperates with other tumor suppressor genes to transform mammary epithelial cells by disrupting cellular differentiation and tissue architecture. Mechanistically, FUBP1 participates in regulating N6-methyladenosine (m6A) RNA methylation, and its loss leads to global changes in RNA splicing and widespread expression of aberrant driver isoforms. These findings suggest that somatic alteration of a single gene involved in RNA splicing and m6A methylation can produce the necessary panoply of contributors for neoplastic transformation. : Elman et al. identify FUBP1 as a long tail cancer driver using a combinatorial CRISPR/Cas9 screen. FUBP1 and PTEN cooperate to transform mammary epithelial cells by disrupting cellular differentiation and tissue architecture. FUBP1−/− cells exhibit decreased m6A RNA methylation, leading to widespread expression of aberrant driver isoforms. Keywords: tumor suppressor gene, breast cancer, mRNA processing, alternative splicing, N6-methyladenosine, m6A, premature polyadenylation, intronic polyadenylation, epitranscriptome, oncogenic cooperation |
| first_indexed | 2024-12-10T06:10:31Z |
| format | Article |
| id | doaj.art-e617fd7258c847d486aa6bcbaa90f6f9 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T06:10:31Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-e617fd7258c847d486aa6bcbaa90f6f92022-12-22T01:59:35ZengElsevierCell Reports2211-12472019-09-01281334353449.e5Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative SplicingJessica S. Elman0Thomas K. Ni1Kristen E. Mengwasser2Dexter Jin3Ania Wronski4Stephen J. Elledge5Charlotte Kuperwasser6Department of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA; Raymond & Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USADepartment of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA; Raymond & Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USADivision of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USAWhitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA; Raymond & Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USADivision of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA, USA; Department of Genetics, Program in Virology, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115, USADepartment of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA; Raymond & Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA; Corresponding authorSummary: Comprehensive sequencing approaches have allowed for the identification of the most frequent contributors to cancer, known as drivers. They have also revealed a class of mutations in understudied, infrequently altered genes, referred to as “long tail” (LT) drivers. A key challenge has been to find clinically relevant LT drivers and to understand how they cooperate to drive disease. Here, we identified far upstream binding protein 1 (FUBP1) as an LT driver using an in vivo CRISPR screen. FUBP1 cooperates with other tumor suppressor genes to transform mammary epithelial cells by disrupting cellular differentiation and tissue architecture. Mechanistically, FUBP1 participates in regulating N6-methyladenosine (m6A) RNA methylation, and its loss leads to global changes in RNA splicing and widespread expression of aberrant driver isoforms. These findings suggest that somatic alteration of a single gene involved in RNA splicing and m6A methylation can produce the necessary panoply of contributors for neoplastic transformation. : Elman et al. identify FUBP1 as a long tail cancer driver using a combinatorial CRISPR/Cas9 screen. FUBP1 and PTEN cooperate to transform mammary epithelial cells by disrupting cellular differentiation and tissue architecture. FUBP1−/− cells exhibit decreased m6A RNA methylation, leading to widespread expression of aberrant driver isoforms. Keywords: tumor suppressor gene, breast cancer, mRNA processing, alternative splicing, N6-methyladenosine, m6A, premature polyadenylation, intronic polyadenylation, epitranscriptome, oncogenic cooperationhttp://www.sciencedirect.com/science/article/pii/S2211124719311088 |
| spellingShingle | Jessica S. Elman Thomas K. Ni Kristen E. Mengwasser Dexter Jin Ania Wronski Stephen J. Elledge Charlotte Kuperwasser Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing Cell Reports |
| title | Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing |
| title_full | Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing |
| title_fullStr | Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing |
| title_full_unstemmed | Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing |
| title_short | Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing |
| title_sort | identification of fubp1 as a long tail cancer driver and widespread regulator of tumor suppressor and oncogene alternative splicing |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719311088 |
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