Editors' ChoiceCancer

EZH2 drives and defines an epigenetic subclass of lung cancer

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Science Translational Medicine  13 Jul 2016:
Vol. 8, Issue 347, pp. 347ec110
DOI: 10.1126/scitranslmed.aah3543

Cancer is caused by molecular alterations to normal host cells, which act together to drive uncontrolled cell self-renewal, growth, invasion, and malignant transformation. Both genomic and epigenomic changes frequently occur in cancer cells, and it is often debated which of these changes are the initial “drivers” of the disease and which are the later consequences, and in which context.

While DNA changes are hardwired, epigenetic modifications can act dynamically by influencing the structure of chromatin and modulating downstream transcriptional changes. Enhancer of zeste homologue 2 (EZH2) is a member of the polycomb repressive complex responsible for histone methylation (H3K27me3) and repression of target gene expression. EZH2 is mutated in a subset of lymphomas and commonly overexpressed across a range of cancers. The role of EZH2 in cancer initiation is not well defined and may be context specific.

In a recent study, Zhang et al. examined the role of EZH2 in the pathogenesis of lung adenocarcinoma. They showed that a genetically engineered mouse model that ubiquitously overexpresses wild-type EZH2 develops multiple tumors including lymphoma, histiocytic sarcoma of the liver, and lung adenomas/adenocarcinomas. Local overexpression of EZH2 in the lung also causes lung adenocarcinomas in approximately 45% of cases. These EZH2 lung cancers demonstrate pathologic and transcriptional changes resembling those in EZH2-overexpressing human tumors and molecularly distinct from KRAS-mutant tumors.

This study provides evidence that EZH2 is a driver of lung cancer formation. The oncogenic role of EZH2 may be different, or less dominant, in the presence of co-occurring early driver genetic alterations. Integrative ChIP-seq analysis in EZH2 tumors revealed the distribution of H3K27me3 and identified EZH2-associated repression of developmental genes and tumor suppressors. Whether these targets are shared with other EZH2 overexpressing tumors is worth exploring. Based on the oncogenic role of EZH2, the investigators developed and tested a new EZH2 inhibitor, JQEZ5. Both knockdown of EZH2 and treatment with JQEZ5 inhibited tumor growth in EZH2-driven lung cancer models.

Overall, this study sheds light on the role of the epigenome in a subset of KRAS wild-type lung cancers and identifies a potentially targetable subclass of lung cancer. This is an exemplary model of translational research in which a combination of tumor modeling, integrative epigenomic analyses, and multiple methods of targeting can be used to identify a driver of cancer and pave the way for potential clinical studies in a molecularly distinct subgroup of patients.

H. Zhang et al., Oncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer. Cancer Discov. 10.1158/2159-8290.CD-16-0164 (2016). [Abstract]

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