The Epigenetic Regulation of KCNA5 in Pediatric Solid Tumors and its Role in Cancer Biology.

Epigenetic repression of a potassium channel gene;KCNA5;promotes cancer cell survival and proliferation;Pharmacy and Pharmacology;Science (General);Health Sciences;Science;Pharmacology

Ryland, Katherine ElizabethCanman, Christine ;

University of Michigan

关键词: Epigenetic repression of a potassium channel gene;    KCNA5;    promotes cancer cell survival and proliferation;    Pharmacy and Pharmacology;    Science (General);    Health Sciences;    Science;    Pharmacology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/111481/keryland_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Regulation of intracellular elemental ion levels is essential for normal cellular homeostasis. Regulation of potassium ion flux impacts many biological processes, such as proliferation and cell survival, therefore it is of particular importance and the link between its dysregulation and disease is unsurprising.Abundant evidence demonstrates that cancer cells hijack the normal physiologic regulation of potassium channels to promote tumor pathogenesis. As potassium channel expression and function is relatively unexplored in cancer, many gaps exist in our understanding of the mechanisms underlying their aberrant regulation. This thesis details a novel mechanism, comprised of two epigenetic components, underlying repression of the Kv1.5 potassium channel-encoding gene, KCNA5, in the pediatric cancers, Ewing Sarcoma and Neuroblastoma. Furthermore, it elucidates the consequence of KCNA5 repression on cancer cell survival and proliferation. Cancer cells are able to resist cell death despite exposure to cell intrinsic and extrinsic stress. This ability to survive is linked to the concentration of intracellular potassium, as high levels of intracellular potassium inhibit caspase activation and promote cell survival. Given the role of potassium in regulating apoptosis, we reasoned that repression of potassium channel genes might play a role in cancer cell survival. In this thesis, we describe our novel finding that polycomb-dependent epigenetic repression of KCNA5 is a mechanism by which cancer cells resist physiological stressors (i.e. hypoxia and growth factor deprivation) and promote cell survival. Potassium flux regulates cell-cycle progression and its dysregulation allows cancer cells to proliferate. In cancer, this dysregulation promotes advancement through cell-cycle checkpoints and sustains proliferative signaling. In this work, we show that the hyper-proliferative phenotype in cancer is partially dependent on silencing of KCNA5, which is caused by DNA hypermethylation. Interestingly, promoters of PcG targets are often subject to aberrant DNA hypermethylation, and this is true of KCNA5. This thesis reveals a key role for suppression of Kv1.5 in cancer pathogenesis and identifies epigenetic mechanisms as mediators of repression. Furthermore, it demonstrates that inhibition of this epigenetic repression sensitizes cancer cells to stress-induced death signals and prevents their hyper-proliferative phenotype. Thus, this thesis supports the potential use of epigenetic modifiers in adjunct cancer therapy.