Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Abstract

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.Implications: 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.

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

“…Knocking down SETD1A reduced the cell growth and metastatic properties of colorectal cancer cells, and had a major impact on attenuating the expression of Wnt/β-catenin genes (Salz et al, 2014b). Reducing SETD1A expression also lowered the metastatic properties of triple negative breast cancer cells, MDA-MB-231 and BT549, and attenuated the expression of matrix metalloproteinases (Salz et al, 2014a).…”

“…and 1B contribute to the genesis of H3K4me3 (Salz et al, 2014a). Knocking down SETD1A reduced the cell growth and metastatic properties of colorectal cancer cells, and had a major impact on attenuating the expression of Wnt/β-catenin genes (Salz et al, 2014b).…”

Epigenetic Modifications: Therapeutic Potential in Cancer

“…Histone lysine methyltransferases (SETD1 and 2) are found as novel tumor suppressors. Downregulation of SETD2 promotes both initiation and progression in leukemia (Zhu et al 2014), whereas hSETD1A controls tumor metastasis by activating MMP expression (Salz et al 2014). An upregulation of EZH2 (Enhancer of Zeste 2, a histone methyltransferase) has been observed in a wide variety of tumors, such as prostate cancer, lymphomas, colorectal and gastric cancer, and bladder and breast cancer.…”

Aberrant expression of SETD1A promotes survival and migration of estrogen receptor α‐positive breast cancer cells

“…19 Additionally, the regulation of multiple matrix metalloproteinase (MMP) genes by SETD1A has been identified as a major mechanism for promoting metastasis of MDA-MB-231 cells. 20 Our recent studies revealed that SETD1A also plays an important role in estrogen-mediated gene expression. 21,22 However, the clinical significance of SETD1A in ER-positive breast cancer, which accounts for over 70% of all breast cancers, is not clear.…”