Effect of SREBP2 silencing on gene expression of THP-1 monocytes under hypoxic condition
Monocyte infiltrate hypoxic tumor center to initiate pro-tumorigenic immune response and angiogenesis, however the detailed mechanism and responsible metabolic pathway was not investigated. Here we report that monocyte macrophage lineage cells are uniquely responsive to hypoxia compared to cancer cells and fibroblasts, upregulating cholesterol biosynthesis through SREBP2 regulation. Disruption of SREBP2 offsets upregulation of hypoxia-induced cholesterol biosynthesis gene expression. In addition, hypoxia-induced SREBP2 activation is lineage-dependent, and this activation is lost when monocyte matures to macrophage, suggesting a metabolic switch during differentiation. Finally, inhibiting cholesterol synthesis using statin reduces tumor burden and infiltration of pro-tumor immune cells into tumor center. In summary, SREBP2 regulated hypoxic response in monocytes are essential for tumor growth and is a potent drug target for novel therapeutic strategies. Overall design: To investigate if SREBP2 is the regulator for hypoxic response in monocyte, we transfected THP-1 cells with siRNA targeting SREBP2. After 48 hours of transfection, THP-1 cells were cultured in either control or hypoxic condition for 24 hours before extraction of total RNA for RNA-seq analysis. We then performed gene expression profiling analysis and pathway analysis using RNA-seq data.