CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells
Abstract High mortality and low response rates in lung cancer patients call for novel therapeutic targets. Data mining of whole-genome genetic dependency screens suggest Cell Division Cycle 40 (CDC40) to be an essential protein for lung cancer cell survival. We characterized CDC40 knockdown effects...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-83337-z |
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| author | Die Hu Brigitte L. Thériault Vida Talebian Laurent Hoffer Julie Owen Justin Lim Benjamin J. Blencowe Evelyne Lima-Fernandes Punit Saraon Richard Marcellus Rima Al-awar |
| author_facet | Die Hu Brigitte L. Thériault Vida Talebian Laurent Hoffer Julie Owen Justin Lim Benjamin J. Blencowe Evelyne Lima-Fernandes Punit Saraon Richard Marcellus Rima Al-awar |
| author_sort | Die Hu |
| collection | DOAJ |
| description | Abstract High mortality and low response rates in lung cancer patients call for novel therapeutic targets. Data mining of whole-genome genetic dependency screens suggest Cell Division Cycle 40 (CDC40) to be an essential protein for lung cancer cell survival. We characterized CDC40 knockdown effects in multiple lung cancer cell lines, revealing induced cell cycle defects that resulted in strong growth inhibition and activation of apoptosis. Global transcriptional and splicing changes were also investigated, where CDC40 knockdown resulted in perturbation of splicing- and translation-related genes as well as more transcripts with intron retention. In the transcript of the cell cycle regulatory protein CDCA5, CDC40 knockdown was shown to induce retention of the first intron, leading to an increase in the unspliced CDCA5 transcript and subsequent decrease in CDCA5 protein expression. Additionally, protein–protein interactions of CDC40 were explored and spliceosome components were found to be its main binding partners, further highlighting the role of CDC40 in splicing. CDC40 mutation analysis suggests that it may be difficult to disrupt key interactions using small molecules within a large complex. Our results demonstrate that CDC40 is essential for lung cancer cell growth, and that its inhibition may represent a viable therapeutic strategy for lung cancer. |
| format | Article |
| id | doaj-art-1a213078b1814ee69ef54ce2f2935dab |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-1a213078b1814ee69ef54ce2f2935dab2025-01-05T12:19:17ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-024-83337-zCDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cellsDie Hu0Brigitte L. Thériault1Vida Talebian2Laurent Hoffer3Julie Owen4Justin Lim5Benjamin J. Blencowe6Evelyne Lima-Fernandes7Punit Saraon8Richard Marcellus9Rima Al-awar10Drug Discovery Program, Ontario Institute for Cancer ResearchDrug Discovery Program, Ontario Institute for Cancer ResearchDrug Discovery Program, Ontario Institute for Cancer ResearchDrug Discovery Program, Ontario Institute for Cancer ResearchDrug Discovery Program, Ontario Institute for Cancer ResearchDonnelly Centre for Cellular and Biomolecular Research, University of TorontoDonnelly Centre for Cellular and Biomolecular Research, University of TorontoDrug Discovery Program, Ontario Institute for Cancer ResearchDrug Discovery Program, Ontario Institute for Cancer ResearchDrug Discovery Program, Ontario Institute for Cancer ResearchDrug Discovery Program, Ontario Institute for Cancer ResearchAbstract High mortality and low response rates in lung cancer patients call for novel therapeutic targets. Data mining of whole-genome genetic dependency screens suggest Cell Division Cycle 40 (CDC40) to be an essential protein for lung cancer cell survival. We characterized CDC40 knockdown effects in multiple lung cancer cell lines, revealing induced cell cycle defects that resulted in strong growth inhibition and activation of apoptosis. Global transcriptional and splicing changes were also investigated, where CDC40 knockdown resulted in perturbation of splicing- and translation-related genes as well as more transcripts with intron retention. In the transcript of the cell cycle regulatory protein CDCA5, CDC40 knockdown was shown to induce retention of the first intron, leading to an increase in the unspliced CDCA5 transcript and subsequent decrease in CDCA5 protein expression. Additionally, protein–protein interactions of CDC40 were explored and spliceosome components were found to be its main binding partners, further highlighting the role of CDC40 in splicing. CDC40 mutation analysis suggests that it may be difficult to disrupt key interactions using small molecules within a large complex. Our results demonstrate that CDC40 is essential for lung cancer cell growth, and that its inhibition may represent a viable therapeutic strategy for lung cancer.https://doi.org/10.1038/s41598-024-83337-z |
| spellingShingle | Die Hu Brigitte L. Thériault Vida Talebian Laurent Hoffer Julie Owen Justin Lim Benjamin J. Blencowe Evelyne Lima-Fernandes Punit Saraon Richard Marcellus Rima Al-awar CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells Scientific Reports |
| title | CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells |
| title_full | CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells |
| title_fullStr | CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells |
| title_full_unstemmed | CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells |
| title_short | CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells |
| title_sort | cdc40 suppression induces cdca5 splicing defects and anti proliferative effects in lung cancer cells |
| url | https://doi.org/10.1038/s41598-024-83337-z |
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