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Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1
Mohaddase Hamidi1, Ainhoa Eriz1, Jone Mitxelena1,2
1Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Bilbao, Spain.
Cancers
|October 14, 2022
Summary
Inhibiting E2F1/E2F2 in prostate cancer (PCa) causes DNA damage and potentiates chemotherapy. E2F1/E2F2 safeguard genome integrity by restraining CDK1/CDK2 activity, offering new therapeutic strategies for PCa.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- E2F1/E2F2 expression correlates with prostate cancer (PCa) malignancy.
- The precise functional role of E2F in PCa progression and genome integrity is not fully understood.
Purpose of the Study:
- To elucidate the mechanisms by which E2F controls genome integrity in PCa.
- To investigate the impact of modulating E2F activity on PCa progression.
Main Methods:
- Analyzed E2F target gene contribution to genome integrity.
- Assessed the effects of E2F inhibition on PCa cell replication stress and DNA damage.
- Investigated the role of E2F in regulating cell cycle kinases (CDK1/CDK2) and DNA damage response pathways (ATR).
- Evaluated combined E2F and ATR inhibition in PCa xenografts.
Main Results:
- Silencing or inhibiting E2F1/E2F2 induced S phase DNA damage and potentiated 5-FU-induced replication stress.
- E2F inhibition downregulated nucleotide biosynthesis genes (TK1, DCK, TYMS) and reduced WEE1 expression, leading to premature CDK1 activation.
- CDK1/CDK2 inhibition prevented E2F loss-induced DNA damage, indicating E2F safeguards genome integrity by restraining CDK1/CDK2.
- Combined E2F and ATR inhibition significantly reduced PCa cell tumorigenicity in vivo.
Conclusions:
- E2F1/E2F2 play a critical role in maintaining prostate cancer genome integrity by restraining CDK1/CDK2 activity.
- Targeting E2F in combination with nucleotide biosynthesis inhibitors or DNA repair modulators can induce catastrophic replication stress for PCa treatment.
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