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

Abstract

Hypoxia is a major factor in tumor progression and resistance to therapies, which involves elevated levels of the transcription factor HIF-1a. Here we report that prostate tumor xenografts express high levels of HIF-1a 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 HIF-1a and this response is abrogated by knockdown of CHIP, but not by E3 ligase VHL or RACK1. HIF-1a degradation is accompanied by loss-of-function, evidenced by reduced expression of HIF-1a dependent genes. CHIP-dependent HIF-1a degradation also occurs in cells arrested in mitosis by nocodazole instead of taxol. Mitotic kinase Aurora B activity is required for taxol-induced HIF-1a degradation. Purified Aurora B directly phosphorylates HIF-1a 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 HIF-1a in prostate cancer cells. This new knowledge may impact the use of mitotic kinase inhibitors and open new approaches for treatment of hypoxic prostate tumors.