CK1 delta restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1 alpha/ARNT complex formation

Abstract

Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1 alpha, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1 delta phosphorylates HIP-la in its N-terminus and reduces its affinity for its heterodimerization partner ARNT. To investigate the importance of this mechanism for cell proliferation under hypoxia, we visually monitored HIP-1 alpha interactions within the cell nucleus using the in situ proximity ligation assay (PIA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1 delta-dependent modification of HIF-1 alpha impairs the formation of a chromatin binding HIF-1 complex. This is confirmed by analyzing expression of lipin-1, a direct target of HIF-1 that mediates hypoxic neutral lipid accumulation. Inhibition of CK1 delta increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1 alpha- and lipin-1-dependent manner. These data reveal a novel role for CK1 delta in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions. (C) 2015 The Authors. Published by Elsevier Inc.