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Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells

DOI: 10.1186/1475-2867-8-15

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Abstract:

We observed differential HKMT expression in a lung cancer model in which normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and Ras were immortal, formed colonies in soft agar, and expressed specific HKMTs for H3 lysine 9 and 27 residues but not for H3 lysine 4 residue. Modifications in the H3 tails affect the binding of proteins to the histone tails and regulate protein function and the position of lysine methylation marks a gene to be either activated or repressed. In the present study, suppression by siRNA of HKMTs (EZH2, G9A, SETDB1 and SUV39H1) that are over-expressed in immortalized and transformed cells lead to reduced cell proliferation and much less anchorage-independent colony growth. We also found that the suppression of H3-K9, G9A and SUV39H1 induced apoptosis and the suppression of H3-K27, EZH2 caused G1 arrest.Our results indicate the potential of these HKMTs in addition to the other targets for epigenetics such as DNMTs and HDACs to be interesting therapeutic targets.Alterations in the processing of the genetic information in carcinogenesis result from stable genetic mutations involving tumor suppressor genes, oncogenes and DNA stability genes as well as from potentially reversible epigenetic changes leading to modifications in gene function [1,2]. It is well established that epigenetic modifications of nucleosomal histones are central to proper gene expression and aberrant DNA methylation of genes play an important role in tumor progression. However, still relatively little is known about histone modifications, especially methylation, with respect to tumorigenesis. The N-terminus of histone tails is modified by amino-acid phosphorylation, acetylation or methylation to form a code for specifying downstream events and consequently a certain chromatin structure. Tens of histone lysine methyltransferases (HKMTs) have been identified and histone lysine methylation is now considered to be a critical regulator of tra

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