hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism

// Mathew Perez-Neut 1 , Vidhya R. Rao 1 and Saverio Gentile 1 1 Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA Correspondence to: Saverio Gentile, email: // Keywords : p21 waf/cip , hERG1/Kv11.1, breast cancer, calmodulin, Ca 2+ -dependent transcription Received : February 23, 2015 Accepted : March 20, 2015 Published : April 12, 2015 Abstract The function of Kv11.1 is emerging in breast cancer biology, as a growing body of evidence indicates that the hERG1/Kv11.1 potassium channel is aberrantly expressed in several cancer types including breast cancers. The biological effects of Kv11.1 channel blockers and their associated side effects are very well known but the potential use of Kv11.1 activators as an anticancer strategy are still unexplored. In our previous work, we have established that stimulation of the Kv11.1 potassium channel activates a senescent-like program that is characterized by a significant increase in tumor suppressor protein levels, such as p21 waf/cip and p16 INK4A . In this study we investigated the mechanism linking Kv11.1 stimulation to augmentation of p21 waf/cip protein level. We have demonstrated that the Kv11.1 channel activator NS1643 activates a calcineurin-dependent transcription of p21 waf/cip and that this event is fundamental for the inhibitory effect of NS1643 on cell proliferation. Our results reveal a novel mechanism by which stimulation of Kv11.1 channel leads to transcription of a potent tumor suppressor and suggest a potential therapeutic use for Kv11.1 channel activators.