Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal
Summary: Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, triggering further studies on understan...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222010768 |
| _version_ | 1828423196275113984 |
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| author | Huiyun Liu Daniel Heller-Trulli Claire L. Moore |
| author_facet | Huiyun Liu Daniel Heller-Trulli Claire L. Moore |
| author_sort | Huiyun Liu |
| collection | DOAJ |
| description | Summary: Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, triggering further studies on understanding CPSF73 regulation and functions in cells. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D leads to CPSF73 downregulation, a pre-mRNA cleavage defect, and dysregulated gene expression in cells. UBE3D dysfunction or chemical inactivation of CPSF73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple-negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down CPSF73 inhibited stem cell renewal properties. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy. |
| first_indexed | 2024-12-10T15:57:56Z |
| format | Article |
| id | doaj.art-2c2c57735bb44f3da83baed9ac1bb5f9 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-10T15:57:56Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-2c2c57735bb44f3da83baed9ac1bb5f92022-12-22T01:42:33ZengElsevieriScience2589-00422022-08-01258104804Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewalHuiyun Liu0Daniel Heller-Trulli1Claire L. Moore2Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USADepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USADepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA; Corresponding authorSummary: Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, triggering further studies on understanding CPSF73 regulation and functions in cells. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D leads to CPSF73 downregulation, a pre-mRNA cleavage defect, and dysregulated gene expression in cells. UBE3D dysfunction or chemical inactivation of CPSF73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple-negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down CPSF73 inhibited stem cell renewal properties. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy.http://www.sciencedirect.com/science/article/pii/S2589004222010768Biological sciencesmolecular biologycell biologycancer |
| spellingShingle | Huiyun Liu Daniel Heller-Trulli Claire L. Moore Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal iScience Biological sciences molecular biology cell biology cancer |
| title | Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal |
| title_full | Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal |
| title_fullStr | Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal |
| title_full_unstemmed | Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal |
| title_short | Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal |
| title_sort | targeting the mrna endonuclease cpsf73 inhibits breast cancer cell migration invasion and self renewal |
| topic | Biological sciences molecular biology cell biology cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222010768 |
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