Microtubule disruption targets HIF-1α mRNA to cytoplasmic P-bodies for translational repression

Abstract

The hypoxia inducible factor 1 alpha (HIF-1 alpha) is overexpressed in solid tumors, driving tumor angiogenesis and survival. However, the mechanisms regulating HIF-1 alpha expression in solid tumors are not fully understood. In this study, we find that microtubule integrity and dynamics are intricately involved in orchestrating HIF-1 alpha translation. HIF-1 alpha messenger RNA (mRNA) traffics on dynamic microtubules when it is actively translated. Microtubule perturbation by taxol (TX) and other microtubule-targeting drugs stalls HIF-1 alpha mRNA transport and releases it from polysomes, suppressing its translation. Immunoprecipitation of the P-body component Argonaute 2 (Ago2) after microtubule disruption shows significant enrichment of HIF-1 alpha mRNAs and HIF-targeting microRNAs (miRNAs). Inhibition of HIF-repressing miRNAs or Ago2 knockdown abrogates TX's ability to suppress HIF-1 alpha translation. Interestingly, microtubule repolymerization after nocodazole washout allows HIF-1 alpha mRNA to reenter active translation, suggesting that microtubule dynamics exert tight yet reversible control over HIF-1 alpha translation. Collectively, we provide evidence for a new mechanism of microtubule-dependent HIF-1 alpha translation with important implications for cell biology.