Abstract
Abstract NSD-1 (Nuclear receptor-binding SET domain protein 1) belongs to the epigenetic family of histone methyltransferases (HMTs), which are frequently found to be mutated in overgrowth syndromes. In cancer, NSD-1 is found as part of fusion proteins (e.g., NUP98-NSD1), which play a major role in the etiology of AML. In contrast to data from hematological tumors, little is known regarding the role of NSD-1 in cancers from solid origin, except that high level expression of NSD-1 has been correlated with poor survival in breast cancer patients (Miller, 2005). NSD-1 over-expression as well as copy number gain for the NSD-1 gene has been described in a variety of tumor cell lines. We studied the role of NSD-1 in the NSCLC line NCI-H460 using an inducible knockdown system (pSLIK). We found that knockdown of NSD-1 (>70% reduction in target mRNA expression) led to a significant decrease in cell proliferation as well as nearly 100% inhibition of anchorage-independent growth, whereas an empty vector transfected stable cell line did not. NSD-1 knockdown induced apoptosis in a time-dependent manner as measured by flow cytometry-based Annexin V staining. Cell death was found to follow a PARP-dependent mechanism suggesting that apoptosis is a contributor to growth inhibition/cell death. By conducting immuno-blot experiments against a panel of histone modifications, we examined putative in vivo histone substrates of NSD1. Our data suggest that NSD1 knockdown in NCI-H460 cells leads to a decrease in histone H4K20 trimethylation (64% inhibition after 24h), but did not affect H3K36 trimethylation as previously reported for NSD1 fusion proteins in AML. Further studies of changes in additional histone modifications are ongoing. In summary, we describe for the first time a functional role for NSD-1 in a NSCLC cell line with implications for this HMT in solid tumor growth/survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4863.
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