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DGCR8 is essential for tumor progression following PTEN loss in the prostate

Cassandra D Belair1, Alireza Paikari2, Felix Moltzahn3

  • 1The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California - San Francisco, San Francisco, CA, USA Center for Reproductive Sciences, University of California - San Francisco, San Francisco, CA, USA Department of Urology, University of California - San Francisco, San Francisco, CA, USA cassandra.belair@ucsf.edu.

EMBO Reports
|July 25, 2015
PubMed

Insights

Deleting the Dgcr8 gene inhibits prostate cancer progression by reducing microRNA levels. This finding reveals microRNAs

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MicroRNA (miRNA) biogenesis machinery is upregulated in human prostate cancer.
  • The Dgcr8 gene is essential for miRNA biogenesis.
  • Pten loss is a key driver of prostate cancer progression.

Purpose of the Study:

  • To investigate the role of Dgcr8 in prostate cancer progression in a Pten-knockout mouse model.
  • To determine the impact of Dgcr8 deletion on tumor development and cellular changes.
  • To explore the relationship between Pten, Dgcr8, and Akt activation in human prostate tumors.

Main Methods:

  • Utilized a Pten-knockout mouse model of prostate cancer.
  • Generated Dgcr8 knockout in the Pten-knockout model.
  • Analyzed tumor progression, cellular compartments (basal-like and luminal), senescence, and proliferation.
  • Sequenced small RNAs to identify miRNA changes.
  • Correlated Dgcr8 mRNA levels with Akt activation in human prostate tumors.

Main Results:

  • Dgcr8 deletion significantly inhibited prostate cancer progression and the development of advanced prostatic intraepithelial neoplasia.
  • Loss of Dgcr8 blocked Pten null-induced expansion of the basal-like cellular compartment.
  • Dgcr8 deletion prevented decreased senescence and increased proliferation observed in late-stage Pten knockout tumors.
  • Numerous miRNA alterations were identified with Pten loss.
  • A strong correlation was found between Akt activation and increased Dgcr8 mRNA levels in human prostate tumors.

Conclusions:

  • MicroRNAs play a critical role in enhancing proliferation and basal cell expansion during prostate cancer progression following Pten loss.
  • Dgcr8 is a key mediator of these microRNA-driven changes.
  • Targeting the miRNA biogenesis pathway, specifically Dgcr8, represents a potential therapeutic strategy for prostate cancer.
Keywords:
DGCR8PTENmicroRNAmicroRNA biogenesisprostate cancer

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