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Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
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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
PubMed

Insights

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.
Keywords:
ATRCDKE2Fapoptosisnucleotide biosynthesisprostate cancerreplication stress

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