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DGCR 8 is essential for tumor progression following PTEN loss in the prostate
Author(s) -
Belair Cassandra D,
Paikari Alireza,
Moltzahn Felix,
Shenoy Archana,
Yau Christina,
Dall'Era Marc,
Simko Jeff,
Benz Christopher,
Blelloch Robert
Publication year - 2015
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201439925
Subject(s) - pten , prostate cancer , prostate , cancer research , biology , medicine , microbiology and biotechnology , cancer , signal transduction , pi3k/akt/mtor pathway
In human prostate cancer, the micro RNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the Dgcr8 gene, a critical component of this complex, inhibits tumor progression in a Pten ‐knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. Dgcr8 loss blocked Pten null‐induced expansion of the basal‐like, but not luminal, cellular compartment. Furthermore, while late‐stage Pten knockout tumors exhibit decreased senescence‐associated beta‐galactosidase activity and increased proliferation, the simultaneous deletion of Dgcr8 blocked these changes resulting in levels similar to wild type. Sequencing of small RNA s in isolated epithelial cells uncovered numerous mi RNA changes associated with PTEN loss. Consistent with a Pten–Dgcr8 association, analysis of a large cohort of human prostate tumors shows a strong correlation between Akt activation and increased Dgcr8 mRNA levels. Together, these findings uncover a critical role for micro RNA s in enhancing proliferation and enabling the expansion of the basal cell compartment associated with tumor progression following Pten loss.