Inhibiting SETD7 methyl‐transferase activity impairs differentiation, lipid metabolism and lactogenesis in mammary epithelial cells

Abstract

SETD7 (SET7/9, KMT7) is a lysine methyltransferase that targets master regulators of cell proliferation and differentiation. Here, the impact of inhibiting SETD7 catalytic activity on mammary epithelial cell differentiation was studied by focusing on genes associated with epithelial differentiation, lactogenesis, and lipid metabolism in HC11 and EpH4 cell lines. Setd7 mRNA and protein levels were induced upon lactogenic differentiation in both cell lines. Inhibition of SETD7 activity by the compound (R)‐PFI‐2 increased cell proliferation and downregulated E‐cadherin, beta‐catenin, lactoferrin, insulin‐like growth factor binding protein 5, and beta‐casein levels. Additionally, inhibition of SETD7 activity affected the lipid profile and altered the mRNA expression of the phospholipid biosynthesis‐related genes choline phosphotransferase 1 and phosphate cytidylyltransferase 2, ethanolamine. Altogether, the results suggest that inhibiting SETD7 catalytic activity impairs mammary epithelial and lactogenic differentiation.

Lysine-specific methyltransferase Set7/9 in stemness, differentiation, and development

“…The role of Set7/9 was also demonstrated for mammary gland epithelium cells (MEC) [ 152 ]. Both Set7/9 mRNA and protein levels increased during differentiation of highly proliferating undifferentiated stem-like cells into differentiated MEC characterized by milk proteins synthesis and lipogenic phenotypes (Fig.…”

“…Inhibition of Set7/9 methyltransferase activity by (R)-PFI-2 enhanced the proliferation and impaired lactogenic differentiation of murine MEC. It was shown that suppression of Set7/9 attenuated the level of H3K4 methylation in chromatin of various differentiation markers, including E-cadherin, beta-catenin, lactoferrin, insulin-like growth factor binding protein 5, and beta-casein [ 152 ]. Additionally, the lipid profile and the expression of phospholipid biosynthesis factors were also altered in Set7/9-suppressed MEC, confirming the importance of Set7/9 in control of differentiation.…”