Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53

With advances in chemically inducedproximity technologies, heterobifunctionalmodalities such as proteolysis targeting chimeras (PROTACs) have beensuccessfully advanced to clinics for treating cancer. However, pharmacologicactivation of tumor-suppressor proteins for cancer treatment remainsa major challenge. Here, we present a novel Acetylation Targeting Chimera (AceTAC) strategy to acetylate the p53 tumor suppressor protein.We discovered and characterized the first p53Y220C AceTAC, MS78, whichrecruits histone acetyltransferase p300/CBP to acetylate the p53Y220Cmutant. MS78 effectively acetylated p53Y220C lysine 382 (K382) ina concentration-, time-, and p300-dependent manner and suppressedproliferation and clonogenicity of cancer cells harboring the p53Y220Cmutation with little toxicity in cancer cells with wild-type p53.RNA-seq studies revealed novel p53Y220C-dependent upregulation ofTRAIL apoptotic genes and downregulation of DNA damage response pathwaysupon acetylation induced by MS78. Altogether, the AceTAC strategycould provide a generalizable platform for targeting proteins, suchas tumor suppressors, via acetylation.

Automated summary

With the novel Acetylation Targeting Chimera (AceTAC) strategy, the p53 tumor suppressor protein can be acetylated successfully. The first p53Y220C AceTAC, MS78, recruits histone acetyltransferase p300/CBP to acetylate the p53Y220C mutant. MS78 effectively suppresses the proliferation and clonogenicity of cancer cells with the p53Y220C mutation and induces upregulation of TRAIL apoptotic genes and downregulation of DNA damage response pathways. In conclusion, the AceTAC strategy provides a generalizable platform for targeting proteins, such as tumor suppressors, via acetylation.