Hypoxia mediates primary cilium disassembly via downregulation of the tumor suppressor CYLD

The primary cilium is becoming popularly known as a tumor suppressor organelle, intricately orchestrating cell cycle progression. Here we show hypoxia mediated HIF‐1α stabilization triggers ciliary disassembly by downregulating the tumor suppressor deubiquitinase CYLD, culminating in induction of HDAC6 activity. Using inner medullary collecting duct cells, IMCD3, we found a decrease in ciliated cell frequency relied on duration of hypoxic exposure. Mechanistic studies investigating ciliary disassembly revealed an inverse relationship between HIF‐1α and CYLD levels. Furthermore, chromatin immunoprecipitation showed a direct interaction between the HIF‐1α protein and the CYLD promoter, supporting the view that CYLD is a direct transcriptional target of HIF‐1α. Our data confirm HIF‐1α transcriptionally represses CYLD by binding to Hypoxia Response Elements in its promoter region. Finally, studies using normal and malignant breast tissue samples provide evidence for HIF‐1α mediated control of ciliogenesis. This is the first report to identify hypoxia as a mediator of ciliary loss by transcriptional repression of CYLD through mechanisms currently under investigation. Our study strengthens the emerging role of the primary cilium as a tumor suppressor and generates compelling evidence for the implication of primary cilia in hypoxia mediated carcinogenesis. Research support funded by NIH/NCI.