Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability

作者：Pattabiraman Diwakar R; Bierie Brian; Kober Katharina Isabelle; Thiru Prathapan; Krall Jordan A; Zill Christina; Reinhardt Ferenc; Tam Wai Leong; Weinberg Robert A^*

来源：Science, 2016, 351(6277): 1042-+.

DOI：10.1126/science.aad3680

The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3', 5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state.

• 出版日期2016-3-4