Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer.
Epigenetic alteration is a hallmark of all cancers. Such alterations lead to modulation of fundamental cancer-related functions, such as proliferation, migration, and invasion. In particular, methylation of Histone H3 Lysine 4 (H3K4), a histone mark generally associated with transcriptional activation, is altered during progression of several human cancers. While the depletion of H3K4 demethylases promotes breast cancer metastasis, the effect of H3K4 methyltransferases on metastasis is not clear. Nevertheless, gene duplications in the human SETD1A (hSETD1A) H3K4 methyltransferase are present in almost half of breast cancers. Herein, expression analysis determined that hSETD1A is upregulated in multiple metastatic human breast cancer cell lines and clinical tumor specimens. Ablation of hSETD1A in breast cancer cells led to a decrease in migration and invasion in vitro and to a decrease in metastasis in nude mice. Furthermore, a group of matrix metalloproteinases (including MMP2, MMP9, MMP12, MMP13, and MMP17) were identified which were downregulated upon depletion of hSETD1A and demonstrated a decrease in H3K4me3 at their proximal promoters based on chromatin immunoprecipitation analysis. These results provide evidence for a functional and mechanistic link among hSETD1A, MMPs, and metastasis in breast cancer, thereby supporting an oncogenic role for hSETD1A in cancer.


CONCLUSIONS
This study reveals that hSETD1A controls tumor metastasis by activating MMP expression and provides an epigenetic link among hSETD1A, MMPs, and metastasis of breast cancer.
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida.
Tal
T
Salz
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida.
Changwang
C
Deng
Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida.
Christine
C
Pampo
Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida. UF Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
Dietmar
D
Siemann
UF Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida. Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida.
Yi
Y
Qiu
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
Kevin
K
Brown
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida. sumingh@ufl.edu.
Suming
S
Huang
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D044127:Epigenesis, Genetic; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D020782:Matrix Metalloproteinases / Q000235:genetics; D008745:Methylation; D051379:Mice; D009362:Neoplasm Metastasis; D015854:Up-Regulation
D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human; D020782:Matrix Metalloproteinases