Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Chemically induced proximity technologies, like PROTACs, have advanced cancer treatment.
• Targeting tumor suppressor proteins for pharmacologic activation remains a challenge in cancer therapy.

Purpose of the Study:

• To introduce a novel AceTAC strategy for targeted protein acetylation.
• To develop and characterize a specific AceTAC for the p53 tumor suppressor protein.

Main Methods:

• Discovery and characterization of the first p53Y220C AceTAC, MS78.
• MS78 was used to recruit histone acetyltransferase p300/CBP for p53Y220C acetylation.
• Assessed MS78's effects on cancer cell proliferation, clonogenicity, and gene expression (RNA-seq).

Main Results:

• MS78 effectively acetylated p53Y220C at K382 in a dose-, time-, and p300-dependent manner.
• MS78 suppressed proliferation and clonogenicity in p53Y220C mutant cancer cells with minimal toxicity to wild-type p53 cells.
• Acetylation by MS78 led to upregulation of TRAIL apoptotic genes and downregulation of DNA damage response pathways.

Conclusions:

• The AceTAC strategy provides a generalizable platform for targeting proteins, including tumor suppressors, through acetylation.
• MS78 demonstrates potential as a therapeutic agent for cancers with p53Y220C mutations.