Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability
Open Access
- 4 March 2016
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 351 (6277), aad3680
- https://doi.org/10.1126/science.aad3680
Abstract
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.Keywords
Funding Information
- National Health and Medical Research Council of Australia (NHMRC APP1071853)
- National Research Foundation, Singapore (NRF-NRFF2015-04)
- National Medical Research Council, Singapore (NMRC/TCR/007-NCC/2013)
- Ludwig Center for Molecular Oncology at MIT
- Breast Cancer Research Foundation
- Samuel Waxman Cancer Research Foundation
- NIH (R01-CA078461)
- American Cancer Society
- D. K. Ludwig Foundation Cancer Research
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