Emerging targets in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is histologically heterogeneous and accounts for 80–85% of lung cancers. Several oncogenic mutations, such as mutations in epidermal growth factor receptor (EGFR) and the tyrosine-protein kinase receptor EML4-ALK, have been identified in patients with NSCLC, and therapies targeting the affected kinase signalling pathways are already in use. Now, Lee and colleagues identify the epigenetic regulator lysine (K)-specific demethylase 2A (KDM2A) as a new potential oncogenic target in NSCLC.

Histone methylation regulates gene expression, and methylated histone H3 lysine 36 (H3K36) has been associated with transcriptional activation. KDM2A is a H3K36-targeting demethylase that the authors found to be overexpressed in several NSCLC cell lines. Moreover, KDM2A mRNA and protein levels were found to be increased in primary NSCLC tumour samples compared with normal lung tissue. Further analysis indicated that the KDM2A gene might be amplified in some patients with NSCLC.

But is there a link between KDM2A overexpression and lung tumorigenesis? Knockdown of KDM2A reduced the proliferation and invasiveness of KDM2A-overexpressing NSCLC cell lines in vitro through a mechanism that was independent of apoptosis or cellular senescence. Importantly, KDM2A silencing inhibited the growth and metastases of NSCLC cells in a mouse tumour xenograft model, which suggested an oncogenic role for KDM2A.

Next, dual specificity phosphatase 3 (DUSP3) was identified as one of the gene targets of KDM2A. Chromatin immunoprecipitation (ChIP) assays indicated that KDM2A localizes at the proximal promoter and 5’ end of DUSP3 and demethelates H3K36 at these sites, thereby repressing DUSP3 expression. Indeed, knockdown of KDM2A in KDM2A-overexpressing NSCLC cell lines increased the protein levels of DUSP3 and decreased the phosphorylation levels of the DUSP3 targets extracellular signal-regulated kinase 1 (ERK1) and ERK2.

ERK1 and ERK2 signalling promotes cell survival and proliferation and, thus, can be oncogenic. Here, the authors showed that KDM2A promotes the proliferation and invasiveness of NSCLC cells through a DUSP3-dependent mechanism that involves deregulation of ERK1 and ERK2 signalling and is independent of EGFR or EML4-ALK signalling. Importantly, high KDM2A protein levels correlated with low DUSP3 protein levels and high phospho-ERK protein levels in primary NSCLC tumour samples, as well as with poor prognosis. Thus, KDM2A could be used as a biomarker in NSCLC prognosis.

Based on their findings, the authors suggest that KDM2A and DUSP3 could be therapeutically targeted in patients with NSCLC that are not eligible for or have gained resistance against the existing targeted therapies.

Maria Papatriantafyllou

Cover image: Wikipedia.

References

Wagner K.W. et al. KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signalling. J. Clin. Invest. 8 Nov 2013. DOI: 10.1172/JCI68642.

Stats

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.