title: Genomic deregulation of the E2F/Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer.
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.
authors: Integrative Oncology Department, BC Cancer Research Centre, Vancouver, Canada.
authors: Bradley P
authors: BP
authors: Coe
authors: Kelsie L
authors: KL
authors: Thu
authors: Sarit
authors: S
authors: Aviel-Ronen
authors: Emily A
authors: EA
authors: Vucic
authors: Adi F
authors: AF
authors: Gazdar
authors: Stephen
authors: S
authors: Lam
authors: Ming-Sound
authors: MS
authors: Tsao
authors: Wan L
authors: WL
authors: Lam
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D016000:Cluster Analysis; D019175:DNA Methylation; D050684:E2F Transcription Factors / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
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