Oncogenic ERG represses PI3K signaling through downregulation of IRS2 Journal Article


Authors: Mao, N.; Gao, D.; Hu, W.; Gadal, S.; Hieronymus, H.; Wang, S.; Lee, Y. S.; Sullivan, P.; Zhang, Z.; Choi, D.; Rosen, N.; Sawyers, C. L.; Gopalan, A.; Chen, Y.; Carver, B. S.
Article Title: Oncogenic ERG represses PI3K signaling through downregulation of IRS2
Abstract: Genomic rearrangements leading to the aberrant expression of ERG are the most common early events in prostate cancer and are significantly enriched for the concomitant loss of PTEN. Genetically engineered mouse models reveal that ERG overexpression alone is not sufficient to induce tumorigenesis, but combined loss of PTEN results in an aggressive invasive phenotype. Here, we show that oncogenic ERG repressed PI3K signaling through direct transcriptional suppression of IRS2, leading to reduced RTK levels and activity. In accordance with this finding, ERG-positive human prostate cancers had a repressed AKT gene signature and transcriptional downregulation of IRS2. Although overexpression of IRS2 activated PI3K signaling, promoting cell migration in a PI3K-dependent manner, this did not fully recapitulate the phenotype seen with loss of PTEN as PI3K signaling is not as robust as observed in the setting of loss of PTEN. Importantly, deletions of the PTEN locus, which promotes active PI3K signaling, were among the most significant copy-number alterations that co-occurred with ERG genomic rearrangements. This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote oncogenic signaling during tumor evolution. © 2020 American Association for Cancer Research.
Keywords: signal transduction; protein kinase b; controlled study; gene mutation; human cell; gene deletion; nonhuman; animal cell; mouse; phenotype; animal tissue; gene overexpression; animal experiment; animal model; gene locus; genetic transcription; tumor xenograft; phosphatidylinositol 3 kinase; prostate cancer; gene activation; gene rearrangement; gene repression; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; carcinogenicity; transcription factor erg; cell migration; down regulation; gene dosage; erg gene; genetic selection; gene activity; insulin receptor substrate 2; akt gene; human; male; priority journal; article; prostate epithelium cell; pi3k gene; irs2 gene
Journal Title: Cancer Research
Volume: 80
Issue: 7
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2020-04-01
Start Page: 1428
End Page: 1437
Language: English
DOI: 10.1158/0008-5472.Can-19-1394
PUBMED: 32015092
PROVIDER: scopus
PMCID: PMC7127960
DOI/URL:
Notes: Article -- Source: Scopus
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MSK Authors
  1. Charles L Sawyers
    184 Sawyers
  2. Neal Rosen
    383 Rosen
  3. Yu Chen
    81 Chen
  4. Anuradha Gopalan
    332 Gopalan
  5. Brett Stewart Carver
    121 Carver
  6. Wenhuo Hu
    41 Hu
  7. Dong Gao
    24 Gao
  8. Zeda Zhang
    8 Zhang
  9. Sunyana   Gadal
    2 Gadal
  10. Ninghui   Mao
    10 Mao
  11. Shangqian   Wang
    16 Wang
  12. Danielle Wai-pui Li
    8 Li
  13. Young Sun Lee
    6 Lee