Aurora B kinase promotes CHIP-dependent degradation of HIF1a in prostate cancer cells.

Hypoxia is a major factor in tumor progression and resistance to therapies, which involves elevated levels of the transcription factor HIF1 alpha. Here, we report that prostate tumor xenografts express high levels of HIF1 alpha and show greatly enhanced growth in response to knockdown of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein). In multiple human prostate cancer cell lines under hypoxia, taxol treatment induces the degradation of HIF1 alpha, and this response is abrogated by knockdown of CHIP, but not by E3 ligase VHL or RACK1. HIF1 alpha degradation is accompanied by loss of function, evidenced by reduced expression of HIF1 alpha-dependent genes. CHIP-dependent HIF1 alpha degradation also occurs in cells arrested in mitosis by nocodazole instead of taxol. Mitotic kinase Aurora B activity is required for taxol-induced HIF1 alpha degradation. Purified Aurora B directly phosphorylates HIF1a alpha at multiple sites, and these modifications enhance its polyubiquitination by CHIP in a purified reconstituted system. Our results show how activation of Aurora B promotes CHIP-dependent degradation of HIF1 alpha in prostate cancer cells. This new knowledge may affect the use of mitotic kinase inhibitors and open new approaches for treatment of hypoxic prostate tumors.