Abstract
The tumor suppressor p53 and the transcriptional repressor Enhancer of Zeste Homolog 2 (EZH2) have both been implicated in the regulation of epithelial-mesenchymal transition (EMT) and tumor metastasis via their impacts on microRNA expression. Here, we report that mutant p53 (mutp53) promotes EMT in endometrial carcinoma (EC) by disrupting p68-Drosha complex assembly. Overexpression of mutp53 has the opposite effect of wild-type p53 (WTp53), repressing miR-26a expression by reducing pri-miR-26a-1 processing in p53-null EC cells. Re-expression of miR-26a in mutp53 EC cells decreases cell invasion and promotes mesenchymal-epithelial transition (MET). Rescuing miR-26a expression also inhibits EZH2, N-cadherin, Vimentin, and Snail expression and induces E-cadherin expression both in vitro and in vivo. Moreover, patients with higher serum miR-26a levels have a better survival rate. These results suggest that p53 gain-of-function mutations accelerate EC tumor progression and metastasis by interfering with Drosha and p68 binding and pri-miR-26a-1 processing, resulting in reduced miR-26a expression and EZH2 overexpression.
Highlights
Endometrial carcinoma (EC) is a common gynecologic malignancy classified into two subtypes, type I and type II [1]
Enhancer of Zeste Homolog 2 (EZH2) expression was positively correlated with mutp53 expression in type II EC (Spearman correlation r = 0.739, Figure 1D)
Integrated genomic characterization of EC indicates that recurrent p53 mutations are common in type II EC (90%) [10], suggesting mutp53 promotes EC progression
Summary
Endometrial carcinoma (EC) is a common gynecologic malignancy classified into two subtypes, type I and type II [1]. Type I EC occurs in ~85% of patients and is often estrogen receptor positive with well-differentiated tumors of low grade and good prognosis. Patients with type II EC tumors have a 5-year survival rate of only 44% [3]. The tumor suppressor p53 is a transcription factor that inhibits malignant transformation by inducing cell cycle arrest, senescence, and apoptosis [4,5,6]. The mutant p53 (mutp53) may lose its tumor-suppressor functions, it may acquire oncogenic gain of function (GOF) [7,8,9]. Integrated genomic characterization of EC tumors revealed that p53 missense mutations were frequent in type II EC, suggesting a role for mutp in EC progression [10]
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