CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells
Die Hu1,2, Brigitte L Thériault1,3, Vida Talebian1
1Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
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.
Insights
Cell Division Cycle 40 (CDC40) is crucial for lung cancer cell survival. Inhibiting CDC40 shows promise as a new therapeutic strategy for lung cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung cancer exhibits high mortality and low treatment response rates, necessitating the identification of novel therapeutic targets.
- Genetic dependency screens highlight Cell Division Cycle 40 (CDC40) as a potentially essential protein for lung cancer cell survival.
Purpose of the Study:
- To investigate the role of CDC40 in lung cancer cell viability and explore its potential as a therapeutic target.
- To characterize the effects of CDC40 knockdown on lung cancer cell proliferation, apoptosis, and gene expression.
Main Methods:
- Utilized whole-genome genetic dependency screens for target identification.
- Performed CDC40 knockdown experiments in multiple lung cancer cell lines.
- Analyzed global transcriptional and splicing changes, including intron retention.
- Investigated protein-protein interactions of CDC40 and analyzed CDC40 mutations.
Main Results:
- CDC40 knockdown induced cell cycle defects, significant growth inhibition, and apoptosis in lung cancer cells.
- Observed widespread alterations in splicing and translation-related gene expression, with increased intron retention.
- Demonstrated that CDC40 knockdown leads to aberrant splicing of the CDCA5 transcript, reducing its protein expression.
- Identified spliceosome components as primary binding partners of CDC40, reinforcing its role in splicing.
Conclusions:
- CDC40 is essential for lung cancer cell growth and survival.
- CDC40's critical role in splicing and its impact on cell cycle regulation suggest it as a promising therapeutic target for lung cancer.
- Targeting CDC40 through inhibition may offer a viable therapeutic strategy for treating lung cancer, despite potential challenges in disrupting its interactions with small molecules.
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