Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Significance The cellular response to hypoxia is regulated by hypoxia-inducible factor-1α and -2α (HIF-1α and -2α). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α (but not with HIF-2α) and promotes tumor growth and angiogenesis. Hypoxia induces a calpain-dependent cleavage of FLNA to generate a fragment that enhances nuclear accumulation of HIF-1α and is corecruited to HIF-1α target promoters, resulting in enhanced gene expression. This mechanism helps to explain why FLNA is upregulated in certain tumors and offers opportunities in targeting the hypoxia signaling pathway therapeutically.