Abstract C27: Activation of PKA induces a mesenchymal-to-epithelial transition and epigenetic reprogramming-mediated loss of tumor initiating ability

Abstract

Abstract Cancer stem cells (CSCs) have emerged in recent years as important targets for cancer therapy owing to their elevated resistance to conventional chemotherapy as well as to tumor-initiating ability that enables them to seed new tumors and thereby drive clinical relapse. The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that confers mesenchymal traits on both normal and neoplastic epithelial cells. By activating EMT programs, carcinoma cells acquire malignancy-associated traits and additionally may become converted into CSC-like cells, as has been shown in many cases. This association between the EMT program and the CSC state has presented an attractive opportunity for drug development and agents that preferentially target more mesenchymal carcinoma cells rather than their epithelial counterparts are highly sought. An alternative therapeutic approach is to convert CSCs to their non-stem cell counterparts through the induction of a mesenchymal-to-epithelial transition (MET). Here we observe that increases in intracellular levels of the second messenger 3'-5'-cyclic adenosine monophosphate (cAMP) and the subsequent activation of protein kinase A (PKA) induces an MET in mesenchymal human mammary epithelial cells and their neoplastic derivatives. The MET-induced differentiation is accompanied by a loss of stem-like properties and tumor-initiating ability, rendering the cells more sensitive to treatment with chemotherapeutic drugs such as doxorubicin and paclitaxel. Upon activation PKA phosphorylates and activates PHF2, a histone H3K9 demethylase, which relieves H3K9me2/3-mediated repression of epithelial genes. Genome-wide occupancy studies of PHF2 reveal that it interacts with numerous genomic loci, relieving their methylation-mediated silencing, enabling the access of epithelial loci to transcription machinery and ultimately, acquisition of an epithelial state. This works presents an attractive strategy to induce an MET through the activation of a histone demethylase that induces widespread epigenomic reprogramming and acquisition of an epithelial state that is more amenable to chemotherapeutic treatment. Citation Format: Diwakar R. Pattabiraman, Robert A. Weinberg. Activation of PKA induces a mesenchymal-to-epithelial transition and epigenetic reprogramming-mediated loss of tumor initiating ability. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C27.