Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis

Abstract

Disruption of the histone modification patterns is one of the most common features of human tumors. However, few genetic alterations in the histone modifier genes have been described in tumorigenesis. Herein we show that the histone methyltransferase SETDB1 undergoes gene amplification in non-small and small lung cancer cell lines and primary tumors. The existence of additional copies of the SETDB1 gene in these transformed cells is associated with higher levels of the corresponding mRNA and protein. From a functional standpoint, the depletion of SETDB1 expression in amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases the tumor invasiveness. The increased gene dosage of SETDB1 is also associated with enhanced sensitivity to the growth inhibitory effect mediated by the SETDB1-interfering drug mithramycin. Overall, the findings identify SETDB1 as a bona fide oncogene undergoing gene amplification-associated activation in lung cancer and suggest its potential for new therapeutic strategies.

H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis

“…Recently, publications have indicated that KMT1E was found to be a bona fide oncogene undergoing gene amplificationassociated activation in lung tumorigenesis (29). The same study also showed that ectopic expression of KMT1E in A549 cells significantly promoted cell invasion.…”

Chromatin signatures of cancer

“…This is consistent with the function of SETDB1 as a H3K9 monomethyltransferase, whereas Suv39h1/2 act as H3K9 di-and trimethylases (Loyola et al 2009). Intriguingly, studies suggest that amplification of SETDB1 may play a role in development of human cancer as well as in a zebrafish model of melanoma (Ceol et al 2011;Rodriguez-Paredes et al 2014). It remains to be examined whether these oncogenic effects may be mediated through abnormal telomere lengthening.…”

KAT6B Is a Tumor Suppressor Histone H3 Lysine 23 Acetyltransferase Undergoing Genomic Loss in Small Cell Lung Cancer

“…Illumina HumanOmni5-Quad (v1) genotyping array was processed as previously described (9). For multiplex ligation-dependent probe amplification (MLPA), genomic DNA was subjected to SALSA probemixes containing probes for the KAT6B gene, in addition to 21 reference probes, and the analyses were performed using Coffalyser.net software (MRC-Holland).…”

“…qRT-PCR, immunoblotting, immunohistochemistry, and chromatin immunoprecipitation (ChIP) assays were performed as previously described (9). For microarray expression array analysis, total RNA from NCI-N417 and HCC-33 cells expressing two different short hairpin RNA (shRNA) sequences against KAT6B and two different scrambled sequences was labeled and hybridized onto a Human Gene Expression G3 v2 60K array following the manufacturer's instructions.…”