Runx1 Role in Epithelial and Cancer Cell Proliferation Implicates Lipid Metabolism and Scd1 and Soat1 Activity

Abstract

The role of lipid metabolism in epithelial stem cell (SC) function and carcinogenesis is poorly understood. The transcription factor Runx1 is known to regulate proliferation in mouse epithelial hair follicle (HF) SCs in vivo and in several mouse and human epithelial cancers. We found a novel subset of in vivo Runx1 HFSC target genes related to lipid metabolism and demonstrated changes in distinct classes of lipids driven by Runx1. Inhibition of lipid-enzymes Scd1 and Soat1 activity synergistically reduces proliferation of mouse skin epithelial cells and of human skin and oral squamous cell carcinoma cultured lines. Varying Runx1 levels induces changes in skin monounsaturated fatty acids (e.g., oleate, a product of Scd1) as shown by our lipidome analysis. Furthermore, varying Runx1 levels, the inhibition of Scd1, or the addition of Scd1-product oleate, individually affects the plasma membrane organization (or fluidity) in mouse keratinocytes. These factors also affect the strength of signal transduction through the membranes for Wnt, a pathway that promotes epithelial (cancer) cell proliferation and HFSC activation. Our working model is that HFSC factor Runx1 modulates the fatty acid production, which affects membrane organization, facilitating signal transduction for rapid proliferation of normal and cancer epithelial cells. Stem Cells 2018;36:1603-1616.

SOAT1 methylation is associated with coronary heart disease

“…In this study we analyzed DNA methylation levels of a subset of candidate genes in patients diagnosed with CHD and control subjects without CHD. All of the genes analyzed in this study were previously reported to have a potential importance in the absorption of the cholesterol [15–17, 19–21]. Our study observed that methylation levels of SOAT1 were relatively lower in patients with CHD than control group.…”

“…Growing evidence indicated that genetic factors may affect the cholesterol absorption in patients with cardiovascular diseases (CVD) [14]. Previous studies have suggested that many of genes such as FLOT1, FLOT2 and SOAT1, were closely associated with the cholesterol absorption [15–17]. We hypothesized that DNA methylation in some of these genes may reduce the absorption of cholesterol, and influence on the development of CHD.…”

Skin vasculature and hair follicle cross-talking associated with stem cell activation and tissue homeostasis

“…Our previous work has shown that Runx1 has pleiotropic cell-autonomous effects on quiescent HFSCs including control of cell cycle factors (Lee et al, 2013), lipid metabolism (Jain et al, 2018), and Wnt signaling (Osorio et al, 2011). These multiple Runx1 functions prime the hair germ cells for proper timing of activation in the subsequent stage of the hair cycle, but are not sufficient for HFSC activation, as we showed previously (Lee et al, 2014).…”

RUNX transcription factors: orchestrators of development

“…Mechanistically, RUNX1 orchestrates HF specification and maturation by modulating Wnt signaling (Osorio et al, 2011), and regulates HFSCs proliferation in a P21 (Cdkn1a)-dependent manner (Hoi et al, 2010;Lee et al, 2013). Additionally, RUNX1 has been implicated in the lipid metabolism of skin epithelial cells by regulating fatty acid production (Jain et al, 2018). Runx1 is also expressed in mouse keratinocytes, where it collaborates with p63 (Trp63) to regulate the balance between proliferation and differentiation (Masse et al, 2012;Qu et al, 2018).…”