Hypoxia induces microtubule rearrangement in intestinal epithelial cells

Microtubules are integral components of the highly regulated and dynamic cytoskeleton, which is vital for cell function and the maintenance of homeostasis. Microtubule disruption is associated with multiple disease states including colorectal cancer and neurodegenerative disorders. Although much is known about the mechanisms by which microtubules are regulated under physiologic conditions, the effect of pathological stimuli and how this contributes to disease progression is less clear. Hypoxia is a prominent microenvironmental feature of a range of pathological states including inflammation, ischemia, neurodegenerative disease, and cancer. However, our knowledge on the effect of hypoxia on microtubules and whether this impacts disease progression remains limited. Understanding the impact of hypoxia on microtubules is therefore of fundamental importance to understanding disease progression mediated by cytoskeletal changes and may identify new therapeutic targets. In this study, we found that hypoxia decreases intestinal epithelial cell migration. This is associated with a rapid and reversible change in microtubule structure. This cytoskeletal rearrangement occurs independently of changes in α-tubulin protein expression or free-to-polymerized α-tubulin ratio and is also independent of the hypoxia-inducible factor 1α (HIF-1α) pathway. Mechanistically, we found that it is hypoxia-induced changes in glycolytic metabolism that mediate the structural rearrangement of α-tubulin. We hypothesize that these data identify a potential opportunity to utilize drugs targeting glycolytic metabolism to sensitize drug-resistant colorectal epithelial cancer cells to microtubule-based chemotherapies.NEW & NOTEWORTHY We found that in response to hypoxia, epithelial cells reorganize their microtubular structure into intense, punctate clusters with no change in polymerization. Furthermore, while this structural rearrangement is rapidly inducible, reversible, and oxygen-dependent, it is mediated in a HIF-1α-independent manner. We noted that PGAM1, a key glycolytic enzyme, facilitates this structural reorganization of the microtubules via association with α-tubulin and its metabolic activity, in response to hypoxia or other forms of glycolytic stress.