The CTCF-H3K27me3 axis supports melanoma cell migration by repressing cholesterol biosynthesis

CTCF is a key factor in three-dimensional chromatin folding and transcriptional control that was found to affect cancer cell migration by a mechanism that is still poorly understood. To identify this mechanism, we used mouse melanoma cells with a partial loss of function (pLoF) of CTCF. We found that CTCF pLoF inhibits cell migration rate while leading to an increase in the expression of multiple enzymes in the cholesterol biosynthesis pathway along with an elevation in the cellular cholesterol levels. Inhibition of cholesterol synthesis in CTCF pLoF cells restored the cellular migration rate, suggesting that CTCF supports cell migration by suppressing cholesterol synthesis. Detailed analysis of the promoter of Hmgcs1, an early enzyme in the cholesterol synthesis pathway, revealed that CTCF enables PRC2 recruitment to the promoter and deposition of H3K27me3 to prevent SREBP2 binding and activation of transcription. By this mechanism CTCF fine-tunes cholesterol levels to support cell migration. Notably, genome wide association studies suggest a link between CTCF and cholesterol-associated diseases, thus CTCF emerges as a new regulator of cholesterol biosynthesis.