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DNA methylation protects cancer cells against senescence

Joint Research Seminar

Event Information

Date and Time 2025/2/17 (Monday) 10:30~ 11:30
Venue Auditorium, Building 1, IMSUT
Speaker Dr. Pierre Defossez
Affiliation/Position CNRS, Paris
Country France
Title DNA methylation protects cancer cells against senescence
Language English
Organizer Atsuya Nishiyama

Overview

DNA methylation is an essential epigenetic mark in mammals. It controls gene expression and genome stability. Global DNA methylation patterns are 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.
 
So far, we have found that UHRF1 or DNMT1 depletion can induce global DNA hypomethylation and cellular senescence. Disturbing DNA methylation is necessary and sufficient for this senescence induction. Intriguingly, UHRF1 depletion leads to more DNA methylation loss, which appears to have a broader impact on transcriptome regulation and phenotypes than DNMT1 depletion. Furthermore, the senescence induced by UHRF1 or DNMT1 depletion is p53/p21 or p16/pRb canonical pathway-independent and did not cause further DNA damage. Notably, the suppression of cyclic GMP–AMP synthase (cGAS) alleviates the senescence-associated secretory phenotype (SASP) and senescence-associated β-galactosidase (SA-β-gal) activity.
 
In conclusion, UHRF1 is an important epigenetic regulator and a cell cycle regulator of CRC cancer cells. It may help cancer cells resist senescence. Blocking UHRF1 could be a promising strategy in antineoplastic therapies.