Oxygen is required for energy production in mammalian cells, one of the essential processes that promote cell survival and ensure normal cell functions. Hypoxia, which is characterized by a decrease in oxygen availability, can occur at different steps of tumor development and is involved in cancer resistance to therapeutic treatments. The master regulator of the adaptive response to hypoxia is HIF-1, which is now a target for cancer therapy. However, while some data show that HIF-1 can control more than 80% of the genes induced under hypoxia, other experiments clearly demonstrate that a part of the hypoxic response is HIF-1 independent. The goal of this study was to identify some of these HIF-1 independent factors and to investigate their functional roles in the adaptation of tumor cells to hypoxia. Using a proteomic approach on human hepatoma cells HepG2, we showed that the cytoplasmic dynein intermediate chain 2 (DH IC-2), a component of an intracellular ATPase minus-end directed tubulin-based motile complex, was upregulated and post-translationally modified under hypoxia in a HIF-1 independent way. We identified this post-translational modification as a phosphorylation by protein kinase C, which is inhibited under hypoxia. In parallel, the migration of HepG2 cells was enhanced under hypoxia. Cell migration was also increased, to the same extent, by the invalidation of DH IC-2 using siRNA under normoxia. Taken together, these results suggest that under hypoxia, a specific modification of DH IC-2 may modulate its activity, and in turn promote cell migration. These results are important for a better understanding of cancer development since they highlight a HIF-1 independent mechanism, which may be involved in metastasis. In parallel, the proteomic approach pointed out clusters of proteins involved in the mRNA biosynthesis, UPR and others stress responses, proteasomal degradation, building and cytoskeleton maturation, etc. If the role of these proteins in cancer HIF-1 independent hypoxic response still need to be ascertained, they may also be a part of the cancer cell adaptation to hypoxia.