Bclaf1 is a direct target of HIF-1 and critically regulates the stability of HIF-1α under hypoxia

Hypoxic stress is intimately connected with tumor progression, with hypoxia-inducible factor-1 alpha (HIF-1 alpha) being a critical regulator in this process. HIF-1 alpha is stabilized in response to hypoxia, which is required for the induction of gene transcriptions important for hypoxic adaptation. Bclaf1 is a multifunctional protein involved in tumorigenesis, however, its role in this process is not well characterized. Here we report Bclaf1 is a direct transcriptional target of HIF-1 and upregulated in multiple cell lines during hypoxia. Importantly, we found Bclaf1 is involved in the stabilization of HIF-1 alpha during long-term hypoxic treatments. Compared with the control cells, the protein level and stability of HIF-1 alpha in Bclaf1 knockdown or knockout cells is greatly compromised after long-term hypoxic treatments, concomitant with the impaired inductions of HIF-1 target gene transcription. Bclaf1 knockout HeLa cells exhibit a reduced tumor growth in mice xenografts, in which the expressions of HIF-1 alpha and its target genes are also decreased. Bclaf1 binds to HIF-1 alpha in the nucleus, and this interaction is required for Bclaf1 to stabilize HIF-1 alpha in hypoxic condition. These results uncover a positive feedback loop, HIF-1-Bclaf1, that sustains HIF-1 activity during long-term hypoxic conditions by binding to and protecting HIF-1 alpha from degradation, and suggest that Bclaf1 may promote tumor progression by enhancing HIF-1 alpha stability.