Hypoxia-induced translation of collagen-modifying enzymes PLOD2 and P4HA1 is dependent on RBM4 and eIF4E2 in human...

Hypoxia is a critical microenvironmental factor that induces tumorigenesis and cancer progression, including metastasis. The highly dynamic nature of the extracellular matrix (ECM) plays a crucial role in metastasis. Collagens are the predominant component of structural proteins embedded within the ECM. The biosynthesis of collagen typically undergoes a series of posttranslational modifications, such as hydroxylation of lysine and proline residues by procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) and prolyl 4-hydroxylases (P4Hs), respectively. Collagen hydroxylation is critical for ECM remodeling and maintenance. We recently investigated hypoxia-induced translation in human colon cancer HCT116 cells and identified several collagen-modifying enzymes, including procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) and prolyl 4-hydroxylase subunit alpha 1 (P4HA1). Although the translation of bulk mRNAs is repressed in hypoxia, specific mRNAs remain efficiently translated under such conditions. We have found that PLOD2 and P4HA1 are significantly upregulated in hypoxic HCT116 cells compared to normoxic cells. HIF-1 is known to induce the transcription of PLOD2 and P4HA1 during hypoxia. However, the molecular mechanisms of hypoxia-induced translation of PLOD2 and P4HA1 remain largely unclear. We provide evidence that RBM4 and eIF4E2 are required for hypoxia-induced translation of PLOD2 and P4HA1 mRNAs. The 3' UTRs of PLOD2 and P4HA1 mRNAs are involved in translational control during hypoxia in HCT116 cells.