Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53

Md Kabir, Ning Sun, Xiaoping Hu, Tiphaine C. Martin, Jingjie Yi, Yue Zhong, Yan Xiong, H. Ümit Kaniskan, Wei Gu, Ramon Parsons, Jian Jin

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

With advances in chemically induced proximity technologies, heterobifunctional modalities such as proteolysis targeting chimeras (PROTACs) have been successfully advanced to clinics for treating cancer. However, pharmacologic activation of tumor-suppressor proteins for cancer treatment remains a 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, which recruits histone acetyltransferase p300/CBP to acetylate the p53Y220C mutant. MS78 effectively acetylated p53Y220C lysine 382 (K382) in a concentration-, time-, and p300-dependent manner and suppressed proliferation and clonogenicity of cancer cells harboring the p53Y220C mutation with little toxicity in cancer cells with wild-type p53. RNA-seq studies revealed novel p53Y220C-dependent upregulation of TRAIL apoptotic genes and downregulation of DNA damage response pathways upon acetylation induced by MS78. Altogether, the AceTAC strategy could provide a generalizable platform for targeting proteins, such as tumor suppressors, via acetylation.

Original languageEnglish
Pages (from-to)14932-14944
Number of pages13
JournalJournal of the American Chemical Society
Volume145
Issue number27
DOIs
StatePublished - 12 Jul 2023

Fingerprint

Dive into the research topics of 'Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53'. Together they form a unique fingerprint.

Cite this