Hypoxic potentiation of cytoskeleton prevents oncogene-induced senescence

Abstract Expression of oncogenes in human primary cells triggers oncogene-induced senescence (OIS). Distinct from other types of senescence, OIS induces dramatic changes in nuclear shape, cytoskeleton, and heterochromatin distribution. We found that ectopic expression of theΔB-Rafoncogene in IMR90 human fibroblasts induced rearrangement of heterochromatin accompanied by weakening of the cytoskeleton and nuclear lamia, all of which hypoxic condition prevented. RNA-seq analyses revealed that genes involved in cytoskeleton organization were repressed during OIS but much less so under hypoxic condition, whereas genes involved with nuclear lamina remained unchanged. By contrast, the protein levels of nuclear lamina constituting proteins, Lamin A, Emerin and Sun1 diminished during OIS but not under hypoxia. We found that maintaining the cytoskeleton is important for hypoxia to protect nuclear integrity and prevent senescence. This study found that treatment with RhoA/ROCK inhibitors such as Y-27632 destabilized not only cytoskeleton but also the nuclear envelope to induce OIS even under hypoxic condition. These findings show that cytoskeletal organization can be a therapeutic target for blocking hypoxic anti-senescence effects.