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

by Selleckchem | Nov 19 2023

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. In addition, inhibition of SETD7 activity affected the lipid profile and altered the mRNA expression of the phospholipid biosynthesis-related genes choline phosphotransferase 1, and ethanolamine-phosphate cytidylyltransferase. Altogether, the results suggest that inhibiting SETD7 catalytic activity impairs mammary epithelial and lactogenic differentiation.

Comments:

The study you described investigates the role of SETD7, a lysine methyltransferase, in mammary epithelial cell differentiation. The researchers inhibited SETD7 activity using a compound called (R)-PFI-2 and studied its impact on gene expression and cell differentiation in HC11 and EpH4 cell lines.

Here are the key findings of the study:

1. **SETD7 Expression during Differentiation:** The levels of Setd7 mRNA and protein were found to increase during lactogenic differentiation in both HC11 and EpH4 cell lines. This suggests that SETD7 might play a role in the differentiation process of mammary epithelial cells.

2. **Impact of Inhibiting SETD7 Activity:**
   - **Increased Cell Proliferation:** Inhibition of SETD7 activity led to increased cell proliferation. This implies that SETD7 normally acts as a regulator to prevent excessive cell growth.

- **Downregulation of Differentiation Markers:** The inhibition downregulated the expression of important markers associated with epithelial differentiation, such as E-cadherin and beta-catenin, as well as lactogenic differentiation markers like lactoferrin, insulin-like growth factor binding protein 5, and beta-casein. This indicates that inhibiting SETD7 affects the differentiation state of mammary epithelial cells.

- **Impact on Lipid Metabolism:** SETD7 inhibition affected the lipid profile and altered the expression of genes related to phospholipid biosynthesis, specifically choline phosphotransferase 1 and ethanolamine-phosphate cytidylyltransferase. This suggests that SETD7 may have a role in regulating lipid metabolism during mammary epithelial cell differentiation.

Altogether, these findings indicate that SETD7 plays a crucial role in regulating mammary epithelial cell differentiation and lactogenic processes. Inhibition of SETD7 activity disrupts these processes, leading to increased cell proliferation, altered expression of differentiation markers, and changes in lipid metabolism. Understanding the molecular mechanisms controlled by SETD7 could provide valuable insights into mammary gland development and related disorders.