title: SUV420H2 suppresses breast cancer cell invasion through down regulation of the SH2 domain-containing focal adhesion protein tensin-3.
abstract: The genome-wide loss of histone H4 lysine 20 tri-methylation (H4K20me3) is observed in multiple types of cancer, including breast tumors. Since H4K20me3 is preferentially targeted to repetitive elements in the pericentromeric and telomeric heterochromatin and plays a role in chromatin integrity, the pathological effects of disrupted H4K20me3 in tumors have been attributed to genomic instability. However, in this report, we show that loss of H4K20me3 modulates gene expression profiles, leading to increased cell invasion. Reduced H4K20me3 levels in tumor cells are often accompanied by a decrease in the expression of the H4K20-specific methyltransferase, SUV420H2. Exogenous delivery of SUV420H2 into MDA-MB-231 human breast cancer cells induced selective and specific changes in the expression of cancer-related genes. One of the most downregulated genes in response to SUV420H2 expression was the Src substrate, tensin-3, a focal adhesion protein that contributes to cancer cell migration. Depletion of tensin-3 suppressed breast cancer cell invasiveness. Furthermore, silencing of tensin-3 was associated with enrichment of H4K20me3 immediately upstream of the tensin-3 transcription start site, suggesting that the loss of H4K20me3 in tumor cells induced the expression of cancer-promoting genes. These findings connect the loss of H4K20me3 with tumor progression, through the transcriptional activation of cancer-promoting genes.
authors: Graduate School of Medicine and Health Science, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yoshimi
authors: Y
authors: Shinchi
authors: Graduate School of Medicine and Health Science, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: mikihieda@gmail.com.
authors: Miki
authors: M
authors: Hieda
authors: Graduate School of Medicine and Health Science, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yu
authors: Y
authors: Nishioka
authors: Graduate School of Medicine and Health Science, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Ayaka
authors: A
authors: Matsumoto
authors: Graduate School of Medicine and Health Science, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yuhki
authors: Y
authors: Yokoyama
authors: Graduate School of Frontier Biosciences, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama, Kanagawa 226-8501, Japan.
authors: Hiroshi
authors: H
authors: Kimura
authors: Graduate School of Medicine and Health Science, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Shuji
authors: S
authors: Matsuura
authors: Graduate School of Medicine and Health Science, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Nariaki
authors: N
authors: Matsuura
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D000070876:Tensins; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000235:genetics
chemical_list: D008840:Microfilament Proteins; C000603370:TNS3 protein, human; D000070876:Tensins; D011495:Histone-Lysine N-Methyltransferase; C542918:KMT5C protein, human
keywords: Breast tumor; Cell invasion; Histone H4K20me3; SUV420H2; Tensin-3