研究セミナー Noncanonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

DNA methylation is an essential epigenetic mark in mammals. It controls gene expression and genome stability. Global DNA methylation pattern is abnormal in cancers. Targeting DNA methylation machinery is used to kill cancer cells. Ubiquitin like with PHD and RING finger domains 1 (UHRF1) is a key epigenetic regulator that recruits and activates DNA methyltransferase 1 (DNMT1), the methylation maintenance enzyme. UHRF1 is a proven oncogene and its overexpression transforms cells in vitro and causes cancer in animal models. Therefore, UHRF1 provides a unique entry point into the links between epigenetics and cancer. However, it is still not fully clear how UHRF1 works in cancer cells; nor is it clear if the direct targeting of this protein can eliminate cancer cells.

To address this question, we put our project in the context of colorectal cancer (CRC), a very common cancer that is strongly driven by epigenetics. Our experimental strategy was to use an advanced chemical/genetic system —the auxin-inducible degron (AID) technology— to study UHRF1 function, whereby the degron-fused protein can be totally and rapidly degraded upon the addition of a small molecule, auxin. We chose the human CRC cell line HCT116 as our model and successfully generated UHRF1-AID and DNMT1-AID. We also integrated bioinformatic tools to decipher the underlying mechanism.