Polycomb-dependent repression of the potassium channel-encoding gene KCNA5 promotes cancer cell survival under conditions of stress

• Published in: Oncogene Vol. 34; no. 35; pp. 4591 - 4600
• Main Authors: Ryland, K E, Svoboda, L K, Vesely, E D, McIntyre, J C, Zhang, L, Martens, J R, Lawlor, E R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-08-2015; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/2; 14/19; 38/77; 45/15; 631/67/2332; Apoptosis; Bmi protein; Cancer; Cell Biology; Cell death; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Chromatin; Ectopic expression; Embryonic Stem Cells - physiology; Epigenetics; Ewing's sarcoma; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes; Genetic aspects; Human Genetics; Human Umbilical Vein Endothelial Cells - physiology; Humans; Hypoxia; Internal Medicine; Kv1.5 Potassium Channel - biosynthesis; Kv1.5 Potassium Channel - genetics; Medicine; Medicine & Public Health; Neuroblastoma; Oncology; original-article; Physiological aspects; Polycomb group proteins; Polycomb-Group Proteins - physiology; Potassium; Potassium channels; Potassium channels (voltage-gated); Proteins; Remission; Stem cells; Stress; Stress (Physiology); Stress, Physiological; Tumorigenicity; Tumors; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.384

Relapse after clinical remission remains a leading cause of cancer-associated death. Although the mechanisms of tumor relapse are complex, the ability of cancer cells to survive physiological stress is a prerequisite for recurrence. Ewing sarcoma (ES) and neuroblastoma (NB) are aggressive cancers that frequently relapse after initial remission. In addition, both tumors overexpress the polycomb group (PcG) proteins BMI-1 and EZH2, which contribute to tumorigenicity. We have discovered that ES and NB resist hypoxic stress-induced death and that survival depends on PcG function. Epigenetic repression of developmental programs is the most well-established cancer-associated function of PcG proteins. However, we noted that voltage-gated potassium (Kv) channel genes are also targets of PcG regulation in stem cells. Given the role of potassium in regulating apoptosis, we reasoned that repression of Kv channel genes might have a role in cancer cell survival. Here we describe our novel finding that PcG-dependent repression of the Kv1.5 channel gene
KCNA5
contributes to cancer cell survival under conditions of stress. We show that survival of cancer cells in stress is dependent upon suppression of Kv1.5 channel function. The
KCNA5
promoter is marked in cancer cells with PcG-dependent chromatin repressive modifications that increase in hypoxia. Genetic and pharmacological inhibition of BMI-1 and EZH2, respectively, restore
KCNA5
expression, which sensitizes cells to stress-induced death. In addition, ectopic expression of the Kv1.5 channel induces apoptotic cell death under conditions of hypoxia. These findings identify a novel role for PcG proteins in promoting cancer cell survival via repression of
KCNA5
.