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.
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