Genomic Deregulation of the E2F/Rb Pathway Leads to Activation of the Oncogene EZH2 in Small Cell Lung Cancer

Bradley P. Coe, Kelsie L. Thu, Sarit Aviel-Ronen, Emily A. Vucic, Adi F. Gazdar, Stephen Lam, Ming Sound Tsao, Wan L. Lam

Research output: Contribution to journalArticle

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Abstract

Small cell lung cancer (SCLC) is a highly aggressive lung neoplasm with extremely poor clinical outcomes and no approved targeted treatments. To elucidate the mechanisms responsible for driving the SCLC phenotype in hopes of revealing novel therapeutic targets, we studied copy number and methylation profiles of SCLC. We found disruption of the E2F/Rb pathway was a prominent feature deregulated in 96% of the SCLC samples investigated and was strongly associated with increased expression of EZH2, an oncogene and core member of the polycomb repressive complex 2 (PRC2). Through its catalytic role in the PRC2 complex, EZH2 normally functions to epigenetically silence genes during development, however, it aberrantly silences genes in human cancers. We provide evidence to support that EZH2 is functionally active in SCLC tumours, exerts pro-tumourigenic functions in vitro, and is associated with aberrant methylation profiles of PRC2 target genes indicative of a "stem-cell like" hypermethylator profile in SCLC tumours. Furthermore, lentiviral-mediated knockdown of EZH2 demonstrated a significant reduction in the growth of SCLC cell lines, suggesting EZH2 has a key role in driving SCLC biology. In conclusion, our data confirm the role of EZH2 as a critical oncogene in SCLC, and lend support to the prioritization of EZH2 as a potential therapeutic target in clinical disease.

Original languageEnglish (US)
Article numbere71670
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 15 2013

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Polycomb Repressive Complex 2
Deregulation
oncogenes
Small Cell Lung Carcinoma
lung neoplasms
Oncogenes
Methylation
Genes
Chemical activation
Cells
genomics
Tumors
cells
Stem cells
methylation
neoplasms
Neoplasms
therapeutics
genes
prioritization

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Genomic Deregulation of the E2F/Rb Pathway Leads to Activation of the Oncogene EZH2 in Small Cell Lung Cancer. / Coe, Bradley P.; Thu, Kelsie L.; Aviel-Ronen, Sarit; Vucic, Emily A.; Gazdar, Adi F.; Lam, Stephen; Tsao, Ming Sound; Lam, Wan L.

In: PLoS One, Vol. 8, No. 8, e71670, 15.08.2013.

Research output: Contribution to journalArticle

Coe, Bradley P. ; Thu, Kelsie L. ; Aviel-Ronen, Sarit ; Vucic, Emily A. ; Gazdar, Adi F. ; Lam, Stephen ; Tsao, Ming Sound ; Lam, Wan L. / Genomic Deregulation of the E2F/Rb Pathway Leads to Activation of the Oncogene EZH2 in Small Cell Lung Cancer. In: PLoS One. 2013 ; Vol. 8, No. 8.
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abstract = "Small cell lung cancer (SCLC) is a highly aggressive lung neoplasm with extremely poor clinical outcomes and no approved targeted treatments. To elucidate the mechanisms responsible for driving the SCLC phenotype in hopes of revealing novel therapeutic targets, we studied copy number and methylation profiles of SCLC. We found disruption of the E2F/Rb pathway was a prominent feature deregulated in 96{\%} of the SCLC samples investigated and was strongly associated with increased expression of EZH2, an oncogene and core member of the polycomb repressive complex 2 (PRC2). Through its catalytic role in the PRC2 complex, EZH2 normally functions to epigenetically silence genes during development, however, it aberrantly silences genes in human cancers. We provide evidence to support that EZH2 is functionally active in SCLC tumours, exerts pro-tumourigenic functions in vitro, and is associated with aberrant methylation profiles of PRC2 target genes indicative of a {"}stem-cell like{"} hypermethylator profile in SCLC tumours. Furthermore, lentiviral-mediated knockdown of EZH2 demonstrated a significant reduction in the growth of SCLC cell lines, suggesting EZH2 has a key role in driving SCLC biology. In conclusion, our data confirm the role of EZH2 as a critical oncogene in SCLC, and lend support to the prioritization of EZH2 as a potential therapeutic target in clinical disease.",
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