Enhanced SMYD3 expression is essential for the growth of breast cancer cells

Abstract

We previously reported that upregulation of SMYD3, a histone H3 lysine-4-specific methyltransferase, plays a key role in the proliferation of colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC). In the present study, we reveal that SMYD3 expression is also elevated in the great majority of breast cancer tissues. Similarly to CRC and HCC, silencing of SMYD3 by small interfering RNA to this gene resulted in the inhibited growth of breast cancer cells, suggesting that increased SMYD3 expression is also essential for the proliferation of breast cancer cells. Moreover, we show here that SMYD3 could promote breast carcinogenesis by directly regulating expression of the proto-oncogene WNT10B. These data imply that augmented SMYD3 expression plays a crucial role in breast carcinogenesis, and that inhibition of SMYD3 should be a novel therapeutic strategy for treatment of breast cancer. (Cancer Sci 2006; 97: 113-118) R ecent molecular studies have disclosed that breast carcinogenesis involves not only genetic alterations in oncogenes and tumor suppressor genes, but also epigenetic dysregulation of a number of genes associated with growth, survival, cell motility and differentiation.(1-3) For example, several oncogenes have been described as being amplified in breast cancer, including HER2, EGFR, MYC, CCND1, Although expression profile analysis using cDNA microarray or DNA chip technology has facilitated the identification of genes with altered expression in cancer, the mechanisms of deregulated expression need to be further investigated. A multistep model of mammary carcinogenesis has been proposed; transformation of normal cells leads to atypical ductal hyperplasia, ductal carcinoma in situ (DCIS), and eventually invasive ductal carcinoma (IDC). However, precise molecular mechanisms underlying breast cancer remain unresolved.Chromatin is composed of genomic DNA and nuclear proteins including histones, and serves as the template for processing genetic information. The dynamic DNA-protein structure of chromatin is influenced by epigenetic modifications on both the DNA and nucleosomal histones. Under the euchromatin state where chromatin forms a relaxed state, the underlying DNA is accesible to transcription factors. In contrast, DNA in the heterochromatin state, where chromatin forms a condensed state, is transcriptionally restricted and thus untranscribed. Recent advances have shown that covalent histone modifications play critical roles in chromatin structure.One of the best-characterized modifications is acetylation, which is controlled by both histone acetyltransferases and deacetylases. Additionally, histone methylation has emerged as another modification that significantly impacts chromatin structure. We reported previously that SMYD3 shows histone H3-K4-specific methyltransferase activity, leading to transcriptional activation of downstream genes including Nkx2.8, and that elevated SMYD3 expression is involved in the growth of human colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC) cells. (14)...

Requirement of Histone Methyltransferase SMYD3 for Estrogen Receptor-mediated Transcription

“…2B). In agreement with previous reports (27,28), our HMT assays showed that histone H3 is specifically methylated by SMYD3 in reconstituted histone octamers (Fig. 2B, lane 4).…”

“…In fact, a microarray analysis of SMYD3-transfected cells has revealed that a large number of genes were up-regulated Ͼ3-fold in the SMYD3-overexpressing cells compared with those in the normal cells (27). Of special relevance to the present study is that the overexpressed levels of SMYD3 have been observed in breast cancer tissues as well as breast cancer cell lines with associated effects on cancer growth (28). ER serves as a sequence-specific transcription factor to regulate a cascade of gene targets whose products mediate the initiation, development, and metastasis of breast cancers.…”

Novobiocin decreases SMYD3 expression and inhibits the migration of MDA‐MB‐231 human breast cancer cells

“…SET and MYND domain-containing protein 3 (SMYD3) was a novel SET-domain-containing protein which was overexpressed in human breast cancer, hepatocellular carcinoma and colorectal carcinoma (6)(7)(8). Previous studies demonstrated that SMYD3 specifically methylates histone H3 at lysine 4 and activates the transcription of a set of downstream genes containing a ''5 0 -CCCTCC-3 0 '' sequence in the promoter region, and these activities require protein cofactors heat-shock protein HSP90.…”

Effects of SMYD3 overexpression on transformation, serum dependence, and apoptosis sensitivity in NIH3T3 cells

“…Recently, a novel SET-domain-containing protein, SET and MYND domain-containing protein 3 (SMYD3) that was overexpressed in human hepatocellular carcinoma, colorectal carcinoma, and breast cancer cell lines, was identified (4)(5)(6). SMYD3 plays an important role in transcriptional regulation as a member of an RNA polymerase complex.…”