Identification of Smyd4 as a Potential Tumor Suppressor Gene Involved in Breast Cancer Development

Abstract

To identify genes involved in breast tumorigenesis, we applied the retroviral LoxP-Cre system to a nontumorigenic mouse mammary epithelial cell line NOG8 to create random chromosome deletion/translocation. We found that the disruption of one allele of Smyd4 (SET and MYND domain containing 4) gene through chromosome translocation led to tumorigenesis. The expression of Smyd4 was markedly decreased in tumor cells. Re-expression of Smyd4 resulted in growth suppression of tumor cells and inhibition of tumor formation in nude mice. Furthermore, the RNA interferencemediated suppression of Smyd4 expression in human MCF10A mammary epithelial cells caused their growth in soft agar. Microarray studies revealed that platelet-derived growth factor receptor A polypeptide (Pdgfr-A) was highly expressed in tumor cells compared with NOG8 cells. Reexpression of Smyd4 significantly reduced the expression of Pdgfr-A in tumor cells. In human breast cancers, reverse transcription-PCR results revealed that Smyd4 expression was totally silenced in 2 of 10 specimens. These findings indicate that Smyd4, as a potential tumor suppressor, plays a critical role in breast carcinogenesis at least partly through inhibiting the expression of Pdgfr-A, and could be a novel target for improving treatment of breast cancer. [Cancer Res 2009;69(9):4067-72]

Structure of Human SMYD2 Protein Reveals the Basis of p53 Tumor Suppressor Methylation

“…Meanwhile, SMYD3 showed no binding activity to any peptide substrates, including H3K36. ITC analysis further confirmed the binding of the p53 peptide (aa 361-380) to SMYD2 with a dissociation constant (K d ) of about 20 M, whereas the binding of histone H3K4 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) peptide to SMYD2 was about 35-fold weaker (Fig. 1, middle right and supplemental Fig.…”

“…Peptides and Antibodies-The following peptides were chemically synthesized (GL Biochem) for histone lysine methyltransferase activity and pull-down assay: H3K4 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), ART-K(me0, me1, me2)QTARKSTGGKAPRKQL; H3K9 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), ARTKQTARK(me0, me1, me2)STGGKAPRKQL; H3K-27 (19 -36), QLATKAARK(me0, me1, me2)SAPATGGVK; H3K36 (26 -46), RKSAPATGGVK(me0, me1, me2)KPHRYRP-GTV; H4K20 (13)(14)(15)(16)(17)(18)(19)(20)…”

“…Less is known about the histone methyltransferase activities and functions of both SMYD4 and SMYD5. However, the former was recently identified as a tumor suppressor gene to regulate the expression of platelet-derived growth factor receptor ␣ polypeptide in breast carcinogenesis (8,9). Together, the published data indicate that this subfamily of enzymes plays diverse roles through methyltransferase activities in regulating cellular functions.…”

The T Allele of rs8075977 in the 5′-Flanking Region of the PEDF Gene Is Associated with Reduced Risk of Coronary Artery Disease in Elderly Chinese Men

“…A drosophila SMYD4 homologue is manifested to be a muscle-specific transcriptional modulator (Thompson and Travers 2008). Additionally, SMYD4 was identified as a potential tumor suppressor in breast cancer (Hu et al 2009), similar to PEDF that is a potential therapeutic target with multiple anti-cancer activities (Ek et al 2006). Although the functions of TLCD2 and SMYD4 need to be further clarified, these researches above seem to associate SNP rs8075977 with PEDF expression more directly and closely.…”

SMYD2 is induced during cell differentiation and participates in early development

“…Similarly to smyd1a/b, smyd3 plays an important role in cardiac and skeletal muscle development in zebrafish (Fujii et al, 2011). In the other hand, SMYD4 is significantly reduced in tumor cells and its re-expression dramatically decreases cancer cell growth (Hu et al, 2009). Also, Drosophila SMYD4 homologue has been involved in muscle development (Thompson and Travers, 2008).…”