Cancer cells escape p53\u2019s tumor suppression through ablation of ZDHHC1-mediated p53 palmitoylation

Jun Tang,Can Xu,Junhao Mu,Tingxiu Xiang,Ailong Huang,Yan Wang,Yixiao Feng,Kang Wang,Ping Ji,Lili Li,Yong Lin,Qin Xiang,Xin Le,Chu-Xia Deng,Weiyan Peng,Ke Xu,Qian Tao

doi:10.1038/s41388-021-01949-5

Abstract

The inactivation of tumor-suppressor genes contributes heavily to oncogenesis. The mutation of TP53 has been well-studied and recognized as a major factor in the development of tumors. Yet other means of p53 inactivation has not been well-elucidated. We previously identified a hypermethylated gene ZDHHC1 that suppresses tumor growth when the expression was restored, but the specific mechanism was yet to be found. The protein product of ZDHHC1 is an S-palmitoyltransferase and we have identified p53 as a substrate for ZDHHC1-mediated palmitoylation, specifically at the C135, C176, and C275 residues. The novel form of post-translational modification of p53 is required for the nuclear translocation of the tumor suppressor. p53 recruited DNMT3A to ZDHHC1 promoter and is responsible for the hypermethylation of ZDHHC1. The epigenetic feedback loop formed by ZDHHC1 and p53 sheds light on the inactivation of p53 without the presence of genetic mutations.

Highlights

Cancer development is a complex process involving oncogene activation and tumor suppressor gene inactivation by genetic and/or epigenetic mechanisms [1]
P53 in turn induced Zinc Finger DHHC-Type Containing 1 (ZDHHC1) hypermethylation by recruiting DNMT3A to the p53 binding motif in the ZDHHC1 promoter. These findings suggest a novel form of post-translational modifications (PTMs) for p53 that is critical in maintaining the activation of the p53 pathway, which is a part of an epigenetic regulatory loop between ZDHHC1 and p53, shedding light on the regulation of p53 pathway without the occurrence of genetic mutations and providing potential therapeutic targets for the battle against cancer
ZDHHC1 is suppressed in TP53WT cancers and ectopic ZDHHC1 inhibits the proliferation of TP53WT cancer cells Our previous work suggested that ZDHHC1 was silenced or downregulated in many cancer cell lines and tissues due to

Summary

Introduction

Cancer development is a complex process involving oncogene activation and tumor suppressor gene inactivation by genetic and/or epigenetic mechanisms [1]. TP53 is one of the most extensively studied tumor suppressor genes whose multifaceted mechanisms involve apoptosis, ferroptosis, DNA repair, genomic stabilization, and angiogenesis [2]. P53 activity is mainly regulated by post-translational modifications (PTMs). P53 protein is activated by phosphorylation and acetylation and inactivated by ubiquitination-mediated proteasomal degradation [4]. When triggers such as DNA damage is induced, p53 is rapidly phosphorylated, which triggers its nuclear translocation to regulate the expression level of its target genes. The current understanding of p53 PTMs fails to translate into effective prevention or treatment of cancers and requires further exploration

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