Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.
The People's Hospital of Suzhou National Hi-Tech District, Suzhou, China.
Cancer Res. 2020 Jun 1;80(11):2175-2189. doi: 10.1158/0008-5472.CAN-19-1912. Epub 2020 Feb 17.
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignant diseases. Multiple studies with large clinic-based cohorts have revealed that variations of phospholipase C epsilon 1 (PLCE1) correlate with esophageal cancer susceptibility. However, the causative role of PLCE1 in ESCC has remained elusive. Here, we observed that hypomethylation-mediated upregulation of PLCE1 expression was implicated in esophageal carcinogenesis and poor prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and promoted p53 ubiquitination, whereas it increased the half-life of mouse double minute 2 homolog (MDM2) and inhibited its ubiquitination, leading to MDM2 stabilization. Mechanistically, the function of PLCE1 correlated with its direct binding to both p53 and MDM2, which promoted MDM2-dependent ubiquitination of p53 and subsequent degradation . Consequently, knockdown of PLCE1 combined with transfection of a recombinant adenoviral vector encoding wild-type p53 resulted in significantly increased levels of autophagy and apoptosis of esophageal cancer . Clinically, the upregulation of PLCE1 and mutant p53 protein predicted poor overall survival of patients with ESCC, and PLCE1 was positively correlated with p53 in ESCC cohorts. Collectively, this work identified an essential role for PLCE1- and MDM2-mediated ubiquitination and degradation of p53 in inhibiting ESCC autophagy and indicates that targeting the PLCE1-MDM2-p53 axis may provide a novel therapeutic approach for ESCC. SIGNIFICANCE: These findings identify hypomethylation-mediated activation of PLCE1 as a potential oncogene that blocks cellular autophagy of esophageal carcinoma by facilitating the MDM2-dependent ubiquitination of p53 and subsequent degradation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2175/F1.large.jpg.
食管鳞状细胞癌（ESCC）是最致命的恶性疾病之一。多项基于大型临床队列的研究表明，磷脂酶 C epsilon 1（PLCE1）的变异与食管癌易感性相关。然而，PLCE1 在 ESCC 中的因果作用仍然难以捉摸。在这里，我们观察到 PLCE1 表达的低甲基化介导上调参与了食管癌变和 ESCC 队列的不良预后。PLCE1 抑制细胞自噬，并抑制 ESCC 中的 p53 和各种 p53 靶向基因的蛋白表达。此外，PLCE1 降低了 p53 的半衰期并促进了 p53 的泛素化，而增加了 mouse double minute 2 homolog（MDM2）的半衰期并抑制了其泛素化，导致 MDM2 稳定。在机制上，PLCE1 的功能与其与 p53 和 MDM2 的直接结合相关，这促进了 MDM2 依赖的 p53 泛素化和随后的降解。因此，PLCE1 的敲低与转染编码野生型 p53 的重组腺病毒载体相结合导致食管癌细胞自噬和凋亡水平显著增加。临床上，PLCE1 和突变型 p53 蛋白的上调预测了 ESCC 患者的总体生存不良，并且在 ESCC 队列中 PLCE1 与 p53 呈正相关。总之，这项工作确定了 PLCE1 和 MDM2 介导的 p53 泛素化和降解在抑制 ESCC 自噬中的重要作用，并表明靶向 PLCE1-MDM2-p53 轴可能为 ESCC 提供一种新的治疗方法。意义：这些发现确定了低甲基化介导的 PLCE1 激活作为一种潜在的癌基因，通过促进 MDM2 依赖的 p53 泛素化和随后的降解，阻断食管癌细胞的细胞自噬。图形摘要：http://cancerres.aacrjournals.org/content/canres/80/11/2175/F1.large.jpg。
