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

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.

小细胞肺癌（Small Cell Lung Cancer, SCLC）是一种侵袭性极强的肺肿瘤，临床结局极差且尚无获批的靶向治疗方案。为阐明驱动SCLC表型的分子机制，以期发现全新治疗靶点，本研究对SCLC的拷贝数与甲基化谱进行了分析。本研究发现，E2F/Rb通路异常是96%受试SCLC样本中出现的显著失调特征，且与EZH2的表达上调密切相关；EZH2是一种癌基因，同时为多梳抑制复合体2（Polycomb Repressive Complex 2, PRC2）的核心成员。EZH2在PRC2复合体中发挥催化功能，正常情况下可在发育过程中对基因进行表观遗传沉默，但在人类癌症中会异常沉默靶基因。本研究提供的证据表明，EZH2在SCLC肿瘤中具有功能活性，可在体外发挥促瘤功能，且与PRC2靶基因的异常甲基化谱密切相关；该异常甲基化谱提示SCLC肿瘤存在“干细胞样”高甲基化特征。此外，慢病毒介导的EZH2敲低实验可显著抑制SCLC细胞系的增殖，这表明EZH2在驱动SCLC发生发展的生物学过程中发挥关键作用。综上，本研究数据证实EZH2是SCLC中的关键癌基因，支持将EZH2列为临床疾病中潜在的优先治疗靶点。