Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1α, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1δ phosphorylates HIF-1α 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 HIF-1α interactions within the cell nucleus using the in situ proximity ligation assay (PLA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1δ-dependent modification of HIF-1α 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 CK1δ increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1α- and lipin-1-dependent manner. These data reveal a novel role for CK1δ in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions.

Colorectal cancer usually develops in clearly defined stages, with distinct molecular alterations characterizing each transition. This often slow process makes colorectal cancer an ideal target for early detection programs. The blossoming of global, -omics approaches in recent years has led to greatly increased expectations for novel diagnostic and prognostic tools. Despite many early disappointments and the resulting skepticism, real progress has been made with exciting new prospects for cancer research. This review summarizes currently available proteomic tools for identifying novel biomarkers and drug targets, as well as an overview of their application in research on molecular mechanisms of carcinogenesis. Emphasis is given to novel sample preparation methods, protein separation and identification techniques, and advanced mass spectrometry tools for quantitative proteomic. The most important applications of these technologies in colorectal cancer research are discussed.

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