Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
Oncogene. 2021 Sep;40(35):5416-5426. doi: 10.1038/s41388-021-01949-5. Epub 2021 Jul 19.
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.
肿瘤抑制基因的失活对肿瘤发生有很大贡献。TP53 的突变已经得到了充分的研究，并被认为是肿瘤发展的一个主要因素。然而，其他 p53 失活的方式还没有得到很好的阐明。我们之前发现了一个高度甲基化的基因 ZDHHC1，当表达恢复时，它可以抑制肿瘤生长，但具体的机制尚不清楚。ZDHHC1 的蛋白产物是一种 S-棕榈酰转移酶，我们已经确定 p53 是 ZDHHC1 介导的棕榈酰化的底物，特别是在 C135、C176 和 C275 残基上。p53 的这种新型翻译后修饰形式是核转位所必需的肿瘤抑制因子。p53 将 DNMT3A 募集到 ZDHHC1 启动子，并负责 ZDHHC1 的高甲基化。由 ZDHHC1 和 p53 形成的表观遗传反馈回路阐明了 p53 失活而没有遗传突变的情况。
