title: Potassium channel KCNA1 modulates oncogene-induced senescence and transformation.
abstract: Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway.
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Lallet-Daher
authors.forename: Clotilde
authors.initials: C
authors.lastname: Wiel
authors.forename: Delphine
authors.initials: D
authors.lastname: Gitenay
authors.forename: Naveenan
authors.initials: N
authors.lastname: Navaratnam
authors.forename: Arnaud
authors.initials: A
authors.lastname: Augert
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Verbeke
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.forename: Sébastien
authors.initials: S
authors.lastname: Aubert
authors.forename: David
authors.initials: D
authors.lastname: Vindrieux
authors.forename: David
authors.initials: D
authors.lastname: Bernard
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051662:Kv1.1 Potassium Channel; D017868:Cyclic AMP-Dependent Protein Kinases